Article

A few years ago, my partner emailed me about a consult.
 

“Dr. Carter, I had the pleasure of seeing Mrs. Smith today for a preconception consult for chronic hypertension. As a high-risk Black woman, she wants to know what we’re going to do to make sure that she doesn’t die in pregnancy or childbirth. I told her that you’re better equipped to answer this question.”

I was early in my career, and the only thing I could assume that equipped me to answer this question over my partners was my identity as a Black woman living in America.

Mrs. Smith was copied on the message and replied with a long list of follow-up questions and a request for an in-person meeting with me. I was conflicted. As a friend, daughter, and mother, I understood her fear and wanted to be there for her. As a newly appointed assistant professor on the tenure track with 20% clinical time, my clinical responsibilities easily exceeded 50% (in part, because I failed to set boundaries). I spent countless hours of uncompensated time serving on diversity, equity, and inclusion initiatives and mentoring and volunteering for multiple community organizations; I was acutely aware that I would be measured against colleagues who rise through the ranks, unencumbered by these social, moral, and ethical responsibilities, collectively known as the “Black tax.”¹

I knew from prior experiences and the tone of Mrs. Smith’s email that it would be a tough, long meeting that would set a precedent of concierge level care that only promised to intensify once she became pregnant. I agonized over my reply. How could I balance providing compassionate care for this patient with my young research program, which I hoped to nurture so that it would one day grow to have population-level impact?

It took me 2 days to finally reply to the message with a kind, but firm, email stating that I would be happy to see her for a follow-up preconception visit. It was my attempt to balance accessibility with boundaries. She did not reply.

Did I fail her?

The fact that I still think of Mrs. Smith may indicate that I did the wrong thing. In fact, writing the first draft of this letter was a therapeutic experience, and I addressed it to Mrs. Smith. As I shared the experience and letter with friends in the field, however, everyone had similar stories. The letter continued to pass between colleagues, who each made it infinitely better. This collective process created the beautiful love letter to Black birthing people that we share here.

We call upon all of our obstetric clinician colleagues to educate themselves to be equally, ethically, and equitably equipped to care for and serve historically marginalized women and birthing people. We hope that this letter will aid in the journey, and we encourage you to share it with patients to open conversations that are too often left closed.

Continue to: Our love letter to Black women and birthing people...

Our love letter to Black women and birthing people

We see you, we hear you, we know you are scared, and we are you. In recent years, the press has amplified gross inequities in maternal care and outcomes that we, as Black birth workers, midwives, and physicians, already knew to be true. We grieve, along with you regarding the recently reported pregnancy-related deaths of Mrs. Kira Johnson,² Dr. Shalon Irving,³ Dr. Chaniece Wallace,⁴ and so many other names we do not know because their stories did not receive national attention, but we know that they represented the best of us, and they are gone too soon. As Black birth workers, midwives, physicians, and more, we have a front-row seat to the United States’ serious obstetric racism, manifested in biased clinical interactions, unjust hospital policies, and an inequitable health care system that leads to disparities in maternal morbidity and mortality for Black women.

Unfortunately, this is not anything new, and the legacy dates back to slavery and the disregard for Black people in this country. What has changed is our increased awareness of these health injustices. This collective consciousness of the risk that is carried with our pregnancies casts a shadow of fear over a period that should be full of the joy and promise of new life. We fear that our personhood will be disregarded, our pain will be ignored, and our voices silenced by a medical system that has sought to dominate our bodies and experiment on them without our permission.⁵ While this history is reprehensible, and our collective risk as Black people is disproportionately high, our purpose in writing this letter is to help Black birthing people recapture the joy and celebration that should be theirs in pregnancy and in the journey to parenthood.

As Black birth workers, we see Black pregnant patients desperately seeking safety, security, and breaking down barriers to find us for their pregnancy care. Often, they are terrified and looking for kinship and community in our offices. In rural areas patients may drive up to 4 hours in distance for an appointment, and during appointments entrust us with their stories of feeling unheard in the medical system. When we anecdotally asked about what they feared about pregnancy, childbirth, and the postpartum period and thought was their risk of dying during pregnancy or childbirth, answers ranged from 1% to 60%. Our actual risk of dying from a pregnancy-related cause, as a Black woman, is 0.0414% (41.4 Black maternal deaths per 100,000 live births).⁶ To put that in perspective, our risk of dying is higher walking down the street or driving a car.⁷

What is the source of the fear? Based on past and present injustices inflicted on people with historically marginalized identities, we have every right to be scared; but, make no mistake that fear comes at a cost, and Black birthing people are the ones paying the bill! Stress and chronic worry are associated with poor pregnancy outcomes, and so this completely justifiable fear, at the population level, is not serving us well personally.⁸ Unfortunately, lost in the messaging about racial inequities in maternal mortality is the reality that the vast majority of Black people and babies will survive, thrive, and have healthy pregnancy outcomes, despite the terrifying population-level statistics and horrific stories of discrimination and neglect that make us feel like our pregnancies and personal peril are synonymous.

While it is true that our absolute individual, personal risk is lower than population-level statistics convey, let us be clear: We are furious about what is happening to Black people! It is immoral that Black patients in the richest country in the world are 3-4 times more likely to die of a pregnancy-related cause than White women,⁹ and we are more likely to experience pregnancy complications and “near misses” when death is narrowly avoided. Research has done an excellent job defining reproductive health disparities in this country, but prioritizing and funding meaningful strategies, policies, and programs to close this gap have not taken precedence—especially initiatives and research that are headed by Black women.^10–12 This is largely because researchers and health care systems continue evaluating strategies that focus on behavior change and narratives that identify individual responsibility as a sole cause of inequity.

Let us be clear, Black people and our behaviors are not the problem.¹³ The problems are White supremacy, classism, sexism, heteropatriarchy, and obstetric racism.^1-21 These must be recognized and addressed across all levels of power. We endorse systems-level changes that are at the root of promoting health equity in our reproductive outcomes. These changes include paid parental leave, Medicaid expansion/extension, reimbursement for doula and lactation services, increased access to perinatal mental health and wellness services, and so much more. (See the Black Mamas Matter Alliance Toolkit: https://blackmamas matter.org/our-work/toolkits/.)

Continue to: Pearls for reassurance...

Pearls for reassurance

While the inequities and their solutions are grounded in the need for systemic change,²² we realize that these population-level solutions feel abstract when our sisters and siblings ask us, “So what can I do to advocate for myself and my baby, right now in this pregnancy?” To be clear, no amount of personal hypervigilance on our part as Black pregnancy-capable people is going to fix these problems, which are systemic; however, we want to provide a few pearls that may be helpful for patient self-advocacy and reassurance:

1. Seek culturally and ethnically congruent care. We intuitively want to find a clinician who looks like us, but sadly, in the United States only 5% of physicians and 2% of midwives are Black. Demand exceeds supply for Black patients who are seeking racially congruent care. Nonetheless, it is critical that you find a physician or midwife who centers you and  provides support and care that affirms the strengths and assets of you, your family, and your community when cultural and ethnic congruency are not possible for you and your pregnancy. 
2. Ask how your clinicians are actively working to ensure optimal and equitable experiences for Black birthing individuals. We recommend asking your clinician and/or hospital what, if anything, they are doing to address health care inequities, obstetric racism, or implicit bias in their pregnancy and postpartum care. Many groups (including some authors of this letter) are working on measures to address obstetric racism. An acknowledgement of initiatives to mitigate inequities is a meaningful first step. You can suggest that they look into it while you explore your options, as this work is rapidly emerging in many areas of the country. 
3. Plan for well-person care. The best time to optimize pregnancy and birth outcomes is before you get pregnant. Set up an appointment with a midwife, ObGyn, or your primary care physician before you get pregnant. Discuss your concerns about pregnancy and use this time to optimize your health. This also provides an opportunity to build a relationship with your physician/ midwife and their group to evaluate whether they curate an environment where you feel seen, heard, and valued when you go for annual exams or problem visits. If you do not get that sense after a couple of visits, find a place where you do. 
4. Advocate for a second opinion. If something does not sound right to you or you have questions that were not adequately answered, it is your prerogative to seek a second opinion; a clinician should never be offended by this. 
5. Consider these factors, for those who deliver in a hospital (by choice or necessity): 

   a. 24/7 access to obstetricians and dedicated anesthesiologists in the hospital

   b. trauma-informed medical/mental health/social services

   c. lactation consultation

   d. supportive trial of labor after cesarean delivery policy

   e. massive blood transfusion  protocol. 

6. Seek doula support! It always helps to have another set of eyes and ears to help advocate for you, especially when you are in pain during pregnancy, childbirth, or in the postpartum period, or are having difficulty advocating for yourself. There is also evidence that women supported by doulas have better pregnancy-related outcomes and experiences.²³ Many major cities in the United States have started to provide race-concordant doula care for Black birthing people  for free.²⁴
7.  Don’t forget about your mental health. As stated, chronic stress from racism impacts birth outcomes. Having a mental health clinician is a great way to mitigate adverse effects of prolonged tension.^25–27
8. Ask your clinician, hospital, or insurance company about participating in group prenatal care and/or nurse home visiting models²⁸ because both are associated with improved birth outcomes.²⁹ Many institutions are implementing group care that provides race-concordant care.^30,31 
9. Ask your clinician, hospital, or local health department for recommendations to a lactation consultant or educator who can support your efforts in breast/ chest/body-feeding. 

We invite you to consider this truth

You, alone, do not carry the entire population-level risk of Black birthing people on your shoulders. We all carry a piece of it. We, along with many allies, advocates, and activists, are outraged and angered by generations of racism and mistreatment of Black birthing people in our health systems and hospitals. We are channeling our frustration and disgust to demand substantive and sustainable change.

Our purpose here is to provide love and reassurance to our sisters and siblings who are going through their pregnancies with thoughts about our nation’s past and present failures to promote health equity for us and our babies. Our purpose is neither to minimize the public health crisis of Black infant and maternal morbidity and mortality nor is it to absolve clinicians, health systems, or governments from taking responsibility for these shameful outcomes or making meaningful changes to address them. In fact, we love taking care of our community by providing the best clinical care we can to our patients. We call upon all of our clinical colleagues to educate themselves to be ethically and equitably equipped to provide health care for Black pregnant patients. Finally, to birthing Black families, please remember this: If you choose to have a baby, the outcome and experience must align with what is right for you and your baby to survive and thrive. So much of the joys of pregnancy have been stolen, but we will recapture the celebration that should be ours in pregnancy and the journey to parenthood.

Sincerely,

Ebony B. Carter, MD, MPH
Maternal Fetal Medicine
Washington University School of Medicine
St. Louis, Missouri

Karen A. Scott, MD, MPH
Birthing Cultural Rigor, LLC
Nashville, Tennessee

Andrea Jackson, MD, MAS
ObGyn
University of California,
San Francisco

Sara Whetstone, MD, MHS
ObGyn
University of California, 
San Francisco

Traci Johnson, MD
ObGyn
University of Missouri 
School of Medicine
Kansas City, Missouri

Sarahn Wheeler, MD
Maternal Fetal Medicine
Duke University School of Medicine
Durham, North Carolina

Asmara Gebre, CNM
Midwife
Zuckerberg San Francisco General Hospital
San Francisco, California

Joia Crear-Perry, MD
ObGyn
National Birth Equity Collaborative
New Orleans, Louisiana

Dineo Khabele, MD
Gynecologic Oncology
Washington University School of Medicine
St. Louis, Missouri

Judette Louis, MD, MPH
Maternal Fetal Medicine
University of South Florida College of Medicine
Tampa, Florida

Yvonne Smith, MSN, RN
Director
Barnes-Jewish Hospital
St. Louis, Missouri

Laura Riley, MD
Maternal Fetal Medicine
Weill Cornell Medicine
New York, New York

Antoinette Liddell, MSN, RN
Care Coordinator
Barnes-Jewish Hospital
St. Louis, Missouri

Cynthia Gyamfi-Bannerman, MD
Maternal Fetal Medicine
Columbia University Irving Medical Center
New York, New York

Rasheda Pippens, MSN, RN
Nurse Educator
Barnes-Jewish Hospital
St. Louis, Missouri

Ayaba Worjoloh-Clemens, MD
ObGyn
Atlanta, Georgia

Allison Bryant, MD, MPH
Maternal Fetal Medicine
Massachusetts General Hospital
Boston, Massachusetts

Sheri L. Foote, CNM
Midwife
Zuckerberg San Francisco General Hospital
San Francisco, California

J. Lindsay Sillas, MD
ObGyn
Bella OB/GYN
Houston, Texas

Cynthia Rogers, MD
Psychiatrist
Washington University School of Medicine
St. Louis, Missouri

Audra R. Meadows, MD, MPH
ObGyn
University of California, San Diego

AeuMuro G. Lake, MD
Urogynecologist
Urogynecology and Healing Arts
Seattle, Washington

Nancy Moore, MSN, RN, WHNP-BC
Nurse Practitioner
Barnes-Jewish Hospital
St. Louis, Missouri

Zoë Julian, MD, MPH
ObGyn
University of Alabama at Birmingham

Janice M. Tinsley, MN, RNC-OB
Zuckerberg San Francisco General Hospital
San Francisco, California

Jamila B. Perritt, MD, MPH
ObGyn
Washington, DC

Joy A. Cooper, MD, MSc
ObGyn
Culture Care
Oakland, California

Arthurine K. Zakama, MD
ObGyn
University of California,San Francisco

Alissa Erogbogbo, MD
OB Hospitalist
Los Altos, California

Sanithia L. Williams, MD
ObGyn
Huntsville, Alabama

Audra Williams, MD, MPH
ObGyn
University of Alabama, Birmingham

Hedwige “Didi” Saint Louis, MD, MPH
OB Hospitalist
Morehouse School of Medicine
Atlanta, Georgia

Cherise Cokley, MD
OB Hospitalist
Community Hospital
Munster, Indiana

J’Leise Sosa, MD, MPH
ObGyn
Buffalo, New York

A few years ago, my partner emailed me about a consult.
 

“Dr. Carter, I had the pleasure of seeing Mrs. Smith today for a preconception consult for chronic hypertension. As a high-risk Black woman, she wants to know what we’re going to do to make sure that she doesn’t die in pregnancy or childbirth. I told her that you’re better equipped to answer this question.”

I was early in my career, and the only thing I could assume that equipped me to answer this question over my partners was my identity as a Black woman living in America.

Mrs. Smith was copied on the message and replied with a long list of follow-up questions and a request for an in-person meeting with me. I was conflicted. As a friend, daughter, and mother, I understood her fear and wanted to be there for her. As a newly appointed assistant professor on the tenure track with 20% clinical time, my clinical responsibilities easily exceeded 50% (in part, because I failed to set boundaries). I spent countless hours of uncompensated time serving on diversity, equity, and inclusion initiatives and mentoring and volunteering for multiple community organizations; I was acutely aware that I would be measured against colleagues who rise through the ranks, unencumbered by these social, moral, and ethical responsibilities, collectively known as the “Black tax.”¹

I knew from prior experiences and the tone of Mrs. Smith’s email that it would be a tough, long meeting that would set a precedent of concierge level care that only promised to intensify once she became pregnant. I agonized over my reply. How could I balance providing compassionate care for this patient with my young research program, which I hoped to nurture so that it would one day grow to have population-level impact?

It took me 2 days to finally reply to the message with a kind, but firm, email stating that I would be happy to see her for a follow-up preconception visit. It was my attempt to balance accessibility with boundaries. She did not reply.

Did I fail her?

The fact that I still think of Mrs. Smith may indicate that I did the wrong thing. In fact, writing the first draft of this letter was a therapeutic experience, and I addressed it to Mrs. Smith. As I shared the experience and letter with friends in the field, however, everyone had similar stories. The letter continued to pass between colleagues, who each made it infinitely better. This collective process created the beautiful love letter to Black birthing people that we share here.

We call upon all of our obstetric clinician colleagues to educate themselves to be equally, ethically, and equitably equipped to care for and serve historically marginalized women and birthing people. We hope that this letter will aid in the journey, and we encourage you to share it with patients to open conversations that are too often left closed.

Continue to: Our love letter to Black women and birthing people...

Our love letter to Black women and birthing people

We see you, we hear you, we know you are scared, and we are you. In recent years, the press has amplified gross inequities in maternal care and outcomes that we, as Black birth workers, midwives, and physicians, already knew to be true. We grieve, along with you regarding the recently reported pregnancy-related deaths of Mrs. Kira Johnson,² Dr. Shalon Irving,³ Dr. Chaniece Wallace,⁴ and so many other names we do not know because their stories did not receive national attention, but we know that they represented the best of us, and they are gone too soon. As Black birth workers, midwives, physicians, and more, we have a front-row seat to the United States’ serious obstetric racism, manifested in biased clinical interactions, unjust hospital policies, and an inequitable health care system that leads to disparities in maternal morbidity and mortality for Black women.

Unfortunately, this is not anything new, and the legacy dates back to slavery and the disregard for Black people in this country. What has changed is our increased awareness of these health injustices. This collective consciousness of the risk that is carried with our pregnancies casts a shadow of fear over a period that should be full of the joy and promise of new life. We fear that our personhood will be disregarded, our pain will be ignored, and our voices silenced by a medical system that has sought to dominate our bodies and experiment on them without our permission.⁵ While this history is reprehensible, and our collective risk as Black people is disproportionately high, our purpose in writing this letter is to help Black birthing people recapture the joy and celebration that should be theirs in pregnancy and in the journey to parenthood.

As Black birth workers, we see Black pregnant patients desperately seeking safety, security, and breaking down barriers to find us for their pregnancy care. Often, they are terrified and looking for kinship and community in our offices. In rural areas patients may drive up to 4 hours in distance for an appointment, and during appointments entrust us with their stories of feeling unheard in the medical system. When we anecdotally asked about what they feared about pregnancy, childbirth, and the postpartum period and thought was their risk of dying during pregnancy or childbirth, answers ranged from 1% to 60%. Our actual risk of dying from a pregnancy-related cause, as a Black woman, is 0.0414% (41.4 Black maternal deaths per 100,000 live births).⁶ To put that in perspective, our risk of dying is higher walking down the street or driving a car.⁷

What is the source of the fear? Based on past and present injustices inflicted on people with historically marginalized identities, we have every right to be scared; but, make no mistake that fear comes at a cost, and Black birthing people are the ones paying the bill! Stress and chronic worry are associated with poor pregnancy outcomes, and so this completely justifiable fear, at the population level, is not serving us well personally.⁸ Unfortunately, lost in the messaging about racial inequities in maternal mortality is the reality that the vast majority of Black people and babies will survive, thrive, and have healthy pregnancy outcomes, despite the terrifying population-level statistics and horrific stories of discrimination and neglect that make us feel like our pregnancies and personal peril are synonymous.

While it is true that our absolute individual, personal risk is lower than population-level statistics convey, let us be clear: We are furious about what is happening to Black people! It is immoral that Black patients in the richest country in the world are 3-4 times more likely to die of a pregnancy-related cause than White women,⁹ and we are more likely to experience pregnancy complications and “near misses” when death is narrowly avoided. Research has done an excellent job defining reproductive health disparities in this country, but prioritizing and funding meaningful strategies, policies, and programs to close this gap have not taken precedence—especially initiatives and research that are headed by Black women.^10–12 This is largely because researchers and health care systems continue evaluating strategies that focus on behavior change and narratives that identify individual responsibility as a sole cause of inequity.

Let us be clear, Black people and our behaviors are not the problem.¹³ The problems are White supremacy, classism, sexism, heteropatriarchy, and obstetric racism.^1-21 These must be recognized and addressed across all levels of power. We endorse systems-level changes that are at the root of promoting health equity in our reproductive outcomes. These changes include paid parental leave, Medicaid expansion/extension, reimbursement for doula and lactation services, increased access to perinatal mental health and wellness services, and so much more. (See the Black Mamas Matter Alliance Toolkit: https://blackmamas matter.org/our-work/toolkits/.)

Continue to: Pearls for reassurance...

Pearls for reassurance

While the inequities and their solutions are grounded in the need for systemic change,²² we realize that these population-level solutions feel abstract when our sisters and siblings ask us, “So what can I do to advocate for myself and my baby, right now in this pregnancy?” To be clear, no amount of personal hypervigilance on our part as Black pregnancy-capable people is going to fix these problems, which are systemic; however, we want to provide a few pearls that may be helpful for patient self-advocacy and reassurance:

1. Seek culturally and ethnically congruent care. We intuitively want to find a clinician who looks like us, but sadly, in the United States only 5% of physicians and 2% of midwives are Black. Demand exceeds supply for Black patients who are seeking racially congruent care. Nonetheless, it is critical that you find a physician or midwife who centers you and  provides support and care that affirms the strengths and assets of you, your family, and your community when cultural and ethnic congruency are not possible for you and your pregnancy. 
2. Ask how your clinicians are actively working to ensure optimal and equitable experiences for Black birthing individuals. We recommend asking your clinician and/or hospital what, if anything, they are doing to address health care inequities, obstetric racism, or implicit bias in their pregnancy and postpartum care. Many groups (including some authors of this letter) are working on measures to address obstetric racism. An acknowledgement of initiatives to mitigate inequities is a meaningful first step. You can suggest that they look into it while you explore your options, as this work is rapidly emerging in many areas of the country. 
3. Plan for well-person care. The best time to optimize pregnancy and birth outcomes is before you get pregnant. Set up an appointment with a midwife, ObGyn, or your primary care physician before you get pregnant. Discuss your concerns about pregnancy and use this time to optimize your health. This also provides an opportunity to build a relationship with your physician/ midwife and their group to evaluate whether they curate an environment where you feel seen, heard, and valued when you go for annual exams or problem visits. If you do not get that sense after a couple of visits, find a place where you do. 
4. Advocate for a second opinion. If something does not sound right to you or you have questions that were not adequately answered, it is your prerogative to seek a second opinion; a clinician should never be offended by this. 
5. Consider these factors, for those who deliver in a hospital (by choice or necessity): 

   a. 24/7 access to obstetricians and dedicated anesthesiologists in the hospital

   b. trauma-informed medical/mental health/social services

   c. lactation consultation

   d. supportive trial of labor after cesarean delivery policy

   e. massive blood transfusion  protocol. 

6. Seek doula support! It always helps to have another set of eyes and ears to help advocate for you, especially when you are in pain during pregnancy, childbirth, or in the postpartum period, or are having difficulty advocating for yourself. There is also evidence that women supported by doulas have better pregnancy-related outcomes and experiences.²³ Many major cities in the United States have started to provide race-concordant doula care for Black birthing people  for free.²⁴
7.  Don’t forget about your mental health. As stated, chronic stress from racism impacts birth outcomes. Having a mental health clinician is a great way to mitigate adverse effects of prolonged tension.^25–27
8. Ask your clinician, hospital, or insurance company about participating in group prenatal care and/or nurse home visiting models²⁸ because both are associated with improved birth outcomes.²⁹ Many institutions are implementing group care that provides race-concordant care.^30,31 
9. Ask your clinician, hospital, or local health department for recommendations to a lactation consultant or educator who can support your efforts in breast/ chest/body-feeding. 

We invite you to consider this truth

You, alone, do not carry the entire population-level risk of Black birthing people on your shoulders. We all carry a piece of it. We, along with many allies, advocates, and activists, are outraged and angered by generations of racism and mistreatment of Black birthing people in our health systems and hospitals. We are channeling our frustration and disgust to demand substantive and sustainable change.

Our purpose here is to provide love and reassurance to our sisters and siblings who are going through their pregnancies with thoughts about our nation’s past and present failures to promote health equity for us and our babies. Our purpose is neither to minimize the public health crisis of Black infant and maternal morbidity and mortality nor is it to absolve clinicians, health systems, or governments from taking responsibility for these shameful outcomes or making meaningful changes to address them. In fact, we love taking care of our community by providing the best clinical care we can to our patients. We call upon all of our clinical colleagues to educate themselves to be ethically and equitably equipped to provide health care for Black pregnant patients. Finally, to birthing Black families, please remember this: If you choose to have a baby, the outcome and experience must align with what is right for you and your baby to survive and thrive. So much of the joys of pregnancy have been stolen, but we will recapture the celebration that should be ours in pregnancy and the journey to parenthood.

Sincerely,

Ebony B. Carter, MD, MPH
Maternal Fetal Medicine
Washington University School of Medicine
St. Louis, Missouri

Karen A. Scott, MD, MPH
Birthing Cultural Rigor, LLC
Nashville, Tennessee

Andrea Jackson, MD, MAS
ObGyn
University of California,
San Francisco

Sara Whetstone, MD, MHS
ObGyn
University of California, 
San Francisco

Traci Johnson, MD
ObGyn
University of Missouri 
School of Medicine
Kansas City, Missouri

Sarahn Wheeler, MD
Maternal Fetal Medicine
Duke University School of Medicine
Durham, North Carolina

Asmara Gebre, CNM
Midwife
Zuckerberg San Francisco General Hospital
San Francisco, California

Joia Crear-Perry, MD
ObGyn
National Birth Equity Collaborative
New Orleans, Louisiana

Dineo Khabele, MD
Gynecologic Oncology
Washington University School of Medicine
St. Louis, Missouri

Judette Louis, MD, MPH
Maternal Fetal Medicine
University of South Florida College of Medicine
Tampa, Florida

Yvonne Smith, MSN, RN
Director
Barnes-Jewish Hospital
St. Louis, Missouri

Laura Riley, MD
Maternal Fetal Medicine
Weill Cornell Medicine
New York, New York

Antoinette Liddell, MSN, RN
Care Coordinator
Barnes-Jewish Hospital
St. Louis, Missouri

Cynthia Gyamfi-Bannerman, MD
Maternal Fetal Medicine
Columbia University Irving Medical Center
New York, New York

Rasheda Pippens, MSN, RN
Nurse Educator
Barnes-Jewish Hospital
St. Louis, Missouri

Ayaba Worjoloh-Clemens, MD
ObGyn
Atlanta, Georgia

Allison Bryant, MD, MPH
Maternal Fetal Medicine
Massachusetts General Hospital
Boston, Massachusetts

Sheri L. Foote, CNM
Midwife
Zuckerberg San Francisco General Hospital
San Francisco, California

J. Lindsay Sillas, MD
ObGyn
Bella OB/GYN
Houston, Texas

Cynthia Rogers, MD
Psychiatrist
Washington University School of Medicine
St. Louis, Missouri

Audra R. Meadows, MD, MPH
ObGyn
University of California, San Diego

AeuMuro G. Lake, MD
Urogynecologist
Urogynecology and Healing Arts
Seattle, Washington

Nancy Moore, MSN, RN, WHNP-BC
Nurse Practitioner
Barnes-Jewish Hospital
St. Louis, Missouri

Zoë Julian, MD, MPH
ObGyn
University of Alabama at Birmingham

Janice M. Tinsley, MN, RNC-OB
Zuckerberg San Francisco General Hospital
San Francisco, California

Jamila B. Perritt, MD, MPH
ObGyn
Washington, DC

Joy A. Cooper, MD, MSc
ObGyn
Culture Care
Oakland, California

Arthurine K. Zakama, MD
ObGyn
University of California,San Francisco

Alissa Erogbogbo, MD
OB Hospitalist
Los Altos, California

Sanithia L. Williams, MD
ObGyn
Huntsville, Alabama

Audra Williams, MD, MPH
ObGyn
University of Alabama, Birmingham

Hedwige “Didi” Saint Louis, MD, MPH
OB Hospitalist
Morehouse School of Medicine
Atlanta, Georgia

Cherise Cokley, MD
OB Hospitalist
Community Hospital
Munster, Indiana

J’Leise Sosa, MD, MPH
ObGyn
Buffalo, New York

A few years ago, my partner emailed me about a consult.
 

“Dr. Carter, I had the pleasure of seeing Mrs. Smith today for a preconception consult for chronic hypertension. As a high-risk Black woman, she wants to know what we’re going to do to make sure that she doesn’t die in pregnancy or childbirth. I told her that you’re better equipped to answer this question.”

I was early in my career, and the only thing I could assume that equipped me to answer this question over my partners was my identity as a Black woman living in America.

Mrs. Smith was copied on the message and replied with a long list of follow-up questions and a request for an in-person meeting with me. I was conflicted. As a friend, daughter, and mother, I understood her fear and wanted to be there for her. As a newly appointed assistant professor on the tenure track with 20% clinical time, my clinical responsibilities easily exceeded 50% (in part, because I failed to set boundaries). I spent countless hours of uncompensated time serving on diversity, equity, and inclusion initiatives and mentoring and volunteering for multiple community organizations; I was acutely aware that I would be measured against colleagues who rise through the ranks, unencumbered by these social, moral, and ethical responsibilities, collectively known as the “Black tax.”¹

I knew from prior experiences and the tone of Mrs. Smith’s email that it would be a tough, long meeting that would set a precedent of concierge level care that only promised to intensify once she became pregnant. I agonized over my reply. How could I balance providing compassionate care for this patient with my young research program, which I hoped to nurture so that it would one day grow to have population-level impact?

It took me 2 days to finally reply to the message with a kind, but firm, email stating that I would be happy to see her for a follow-up preconception visit. It was my attempt to balance accessibility with boundaries. She did not reply.

Did I fail her?

The fact that I still think of Mrs. Smith may indicate that I did the wrong thing. In fact, writing the first draft of this letter was a therapeutic experience, and I addressed it to Mrs. Smith. As I shared the experience and letter with friends in the field, however, everyone had similar stories. The letter continued to pass between colleagues, who each made it infinitely better. This collective process created the beautiful love letter to Black birthing people that we share here.

We call upon all of our obstetric clinician colleagues to educate themselves to be equally, ethically, and equitably equipped to care for and serve historically marginalized women and birthing people. We hope that this letter will aid in the journey, and we encourage you to share it with patients to open conversations that are too often left closed.

Continue to: Our love letter to Black women and birthing people...

Our love letter to Black women and birthing people

We see you, we hear you, we know you are scared, and we are you. In recent years, the press has amplified gross inequities in maternal care and outcomes that we, as Black birth workers, midwives, and physicians, already knew to be true. We grieve, along with you regarding the recently reported pregnancy-related deaths of Mrs. Kira Johnson,² Dr. Shalon Irving,³ Dr. Chaniece Wallace,⁴ and so many other names we do not know because their stories did not receive national attention, but we know that they represented the best of us, and they are gone too soon. As Black birth workers, midwives, physicians, and more, we have a front-row seat to the United States’ serious obstetric racism, manifested in biased clinical interactions, unjust hospital policies, and an inequitable health care system that leads to disparities in maternal morbidity and mortality for Black women.

Unfortunately, this is not anything new, and the legacy dates back to slavery and the disregard for Black people in this country. What has changed is our increased awareness of these health injustices. This collective consciousness of the risk that is carried with our pregnancies casts a shadow of fear over a period that should be full of the joy and promise of new life. We fear that our personhood will be disregarded, our pain will be ignored, and our voices silenced by a medical system that has sought to dominate our bodies and experiment on them without our permission.⁵ While this history is reprehensible, and our collective risk as Black people is disproportionately high, our purpose in writing this letter is to help Black birthing people recapture the joy and celebration that should be theirs in pregnancy and in the journey to parenthood.

As Black birth workers, we see Black pregnant patients desperately seeking safety, security, and breaking down barriers to find us for their pregnancy care. Often, they are terrified and looking for kinship and community in our offices. In rural areas patients may drive up to 4 hours in distance for an appointment, and during appointments entrust us with their stories of feeling unheard in the medical system. When we anecdotally asked about what they feared about pregnancy, childbirth, and the postpartum period and thought was their risk of dying during pregnancy or childbirth, answers ranged from 1% to 60%. Our actual risk of dying from a pregnancy-related cause, as a Black woman, is 0.0414% (41.4 Black maternal deaths per 100,000 live births).⁶ To put that in perspective, our risk of dying is higher walking down the street or driving a car.⁷

What is the source of the fear? Based on past and present injustices inflicted on people with historically marginalized identities, we have every right to be scared; but, make no mistake that fear comes at a cost, and Black birthing people are the ones paying the bill! Stress and chronic worry are associated with poor pregnancy outcomes, and so this completely justifiable fear, at the population level, is not serving us well personally.⁸ Unfortunately, lost in the messaging about racial inequities in maternal mortality is the reality that the vast majority of Black people and babies will survive, thrive, and have healthy pregnancy outcomes, despite the terrifying population-level statistics and horrific stories of discrimination and neglect that make us feel like our pregnancies and personal peril are synonymous.

While it is true that our absolute individual, personal risk is lower than population-level statistics convey, let us be clear: We are furious about what is happening to Black people! It is immoral that Black patients in the richest country in the world are 3-4 times more likely to die of a pregnancy-related cause than White women,⁹ and we are more likely to experience pregnancy complications and “near misses” when death is narrowly avoided. Research has done an excellent job defining reproductive health disparities in this country, but prioritizing and funding meaningful strategies, policies, and programs to close this gap have not taken precedence—especially initiatives and research that are headed by Black women.^10–12 This is largely because researchers and health care systems continue evaluating strategies that focus on behavior change and narratives that identify individual responsibility as a sole cause of inequity.

Let us be clear, Black people and our behaviors are not the problem.¹³ The problems are White supremacy, classism, sexism, heteropatriarchy, and obstetric racism.^1-21 These must be recognized and addressed across all levels of power. We endorse systems-level changes that are at the root of promoting health equity in our reproductive outcomes. These changes include paid parental leave, Medicaid expansion/extension, reimbursement for doula and lactation services, increased access to perinatal mental health and wellness services, and so much more. (See the Black Mamas Matter Alliance Toolkit: https://blackmamas matter.org/our-work/toolkits/.)

Continue to: Pearls for reassurance...

Pearls for reassurance

While the inequities and their solutions are grounded in the need for systemic change,²² we realize that these population-level solutions feel abstract when our sisters and siblings ask us, “So what can I do to advocate for myself and my baby, right now in this pregnancy?” To be clear, no amount of personal hypervigilance on our part as Black pregnancy-capable people is going to fix these problems, which are systemic; however, we want to provide a few pearls that may be helpful for patient self-advocacy and reassurance:

1. Seek culturally and ethnically congruent care. We intuitively want to find a clinician who looks like us, but sadly, in the United States only 5% of physicians and 2% of midwives are Black. Demand exceeds supply for Black patients who are seeking racially congruent care. Nonetheless, it is critical that you find a physician or midwife who centers you and  provides support and care that affirms the strengths and assets of you, your family, and your community when cultural and ethnic congruency are not possible for you and your pregnancy. 
2. Ask how your clinicians are actively working to ensure optimal and equitable experiences for Black birthing individuals. We recommend asking your clinician and/or hospital what, if anything, they are doing to address health care inequities, obstetric racism, or implicit bias in their pregnancy and postpartum care. Many groups (including some authors of this letter) are working on measures to address obstetric racism. An acknowledgement of initiatives to mitigate inequities is a meaningful first step. You can suggest that they look into it while you explore your options, as this work is rapidly emerging in many areas of the country. 
3. Plan for well-person care. The best time to optimize pregnancy and birth outcomes is before you get pregnant. Set up an appointment with a midwife, ObGyn, or your primary care physician before you get pregnant. Discuss your concerns about pregnancy and use this time to optimize your health. This also provides an opportunity to build a relationship with your physician/ midwife and their group to evaluate whether they curate an environment where you feel seen, heard, and valued when you go for annual exams or problem visits. If you do not get that sense after a couple of visits, find a place where you do. 
4. Advocate for a second opinion. If something does not sound right to you or you have questions that were not adequately answered, it is your prerogative to seek a second opinion; a clinician should never be offended by this. 
5. Consider these factors, for those who deliver in a hospital (by choice or necessity): 

   a. 24/7 access to obstetricians and dedicated anesthesiologists in the hospital

   b. trauma-informed medical/mental health/social services

   c. lactation consultation

   d. supportive trial of labor after cesarean delivery policy

   e. massive blood transfusion  protocol. 

6. Seek doula support! It always helps to have another set of eyes and ears to help advocate for you, especially when you are in pain during pregnancy, childbirth, or in the postpartum period, or are having difficulty advocating for yourself. There is also evidence that women supported by doulas have better pregnancy-related outcomes and experiences.²³ Many major cities in the United States have started to provide race-concordant doula care for Black birthing people  for free.²⁴
7.  Don’t forget about your mental health. As stated, chronic stress from racism impacts birth outcomes. Having a mental health clinician is a great way to mitigate adverse effects of prolonged tension.^25–27
8. Ask your clinician, hospital, or insurance company about participating in group prenatal care and/or nurse home visiting models²⁸ because both are associated with improved birth outcomes.²⁹ Many institutions are implementing group care that provides race-concordant care.^30,31 
9. Ask your clinician, hospital, or local health department for recommendations to a lactation consultant or educator who can support your efforts in breast/ chest/body-feeding. 

We invite you to consider this truth

You, alone, do not carry the entire population-level risk of Black birthing people on your shoulders. We all carry a piece of it. We, along with many allies, advocates, and activists, are outraged and angered by generations of racism and mistreatment of Black birthing people in our health systems and hospitals. We are channeling our frustration and disgust to demand substantive and sustainable change.

Our purpose here is to provide love and reassurance to our sisters and siblings who are going through their pregnancies with thoughts about our nation’s past and present failures to promote health equity for us and our babies. Our purpose is neither to minimize the public health crisis of Black infant and maternal morbidity and mortality nor is it to absolve clinicians, health systems, or governments from taking responsibility for these shameful outcomes or making meaningful changes to address them. In fact, we love taking care of our community by providing the best clinical care we can to our patients. We call upon all of our clinical colleagues to educate themselves to be ethically and equitably equipped to provide health care for Black pregnant patients. Finally, to birthing Black families, please remember this: If you choose to have a baby, the outcome and experience must align with what is right for you and your baby to survive and thrive. So much of the joys of pregnancy have been stolen, but we will recapture the celebration that should be ours in pregnancy and the journey to parenthood.

Sincerely,

Ebony B. Carter, MD, MPH
Maternal Fetal Medicine
Washington University School of Medicine
St. Louis, Missouri

Karen A. Scott, MD, MPH
Birthing Cultural Rigor, LLC
Nashville, Tennessee

Andrea Jackson, MD, MAS
ObGyn
University of California,
San Francisco

Sara Whetstone, MD, MHS
ObGyn
University of California, 
San Francisco

Traci Johnson, MD
ObGyn
University of Missouri 
School of Medicine
Kansas City, Missouri

Sarahn Wheeler, MD
Maternal Fetal Medicine
Duke University School of Medicine
Durham, North Carolina

Asmara Gebre, CNM
Midwife
Zuckerberg San Francisco General Hospital
San Francisco, California

Joia Crear-Perry, MD
ObGyn
National Birth Equity Collaborative
New Orleans, Louisiana

Dineo Khabele, MD
Gynecologic Oncology
Washington University School of Medicine
St. Louis, Missouri

Judette Louis, MD, MPH
Maternal Fetal Medicine
University of South Florida College of Medicine
Tampa, Florida

Yvonne Smith, MSN, RN
Director
Barnes-Jewish Hospital
St. Louis, Missouri

Laura Riley, MD
Maternal Fetal Medicine
Weill Cornell Medicine
New York, New York

Antoinette Liddell, MSN, RN
Care Coordinator
Barnes-Jewish Hospital
St. Louis, Missouri

Cynthia Gyamfi-Bannerman, MD
Maternal Fetal Medicine
Columbia University Irving Medical Center
New York, New York

Rasheda Pippens, MSN, RN
Nurse Educator
Barnes-Jewish Hospital
St. Louis, Missouri

Ayaba Worjoloh-Clemens, MD
ObGyn
Atlanta, Georgia

Allison Bryant, MD, MPH
Maternal Fetal Medicine
Massachusetts General Hospital
Boston, Massachusetts

Sheri L. Foote, CNM
Midwife
Zuckerberg San Francisco General Hospital
San Francisco, California

J. Lindsay Sillas, MD
ObGyn
Bella OB/GYN
Houston, Texas

Cynthia Rogers, MD
Psychiatrist
Washington University School of Medicine
St. Louis, Missouri

Audra R. Meadows, MD, MPH
ObGyn
University of California, San Diego

AeuMuro G. Lake, MD
Urogynecologist
Urogynecology and Healing Arts
Seattle, Washington

Nancy Moore, MSN, RN, WHNP-BC
Nurse Practitioner
Barnes-Jewish Hospital
St. Louis, Missouri

Zoë Julian, MD, MPH
ObGyn
University of Alabama at Birmingham

Janice M. Tinsley, MN, RNC-OB
Zuckerberg San Francisco General Hospital
San Francisco, California

Jamila B. Perritt, MD, MPH
ObGyn
Washington, DC

Joy A. Cooper, MD, MSc
ObGyn
Culture Care
Oakland, California

Arthurine K. Zakama, MD
ObGyn
University of California,San Francisco

Alissa Erogbogbo, MD
OB Hospitalist
Los Altos, California

Sanithia L. Williams, MD
ObGyn
Huntsville, Alabama

Audra Williams, MD, MPH
ObGyn
University of Alabama, Birmingham

Hedwige “Didi” Saint Louis, MD, MPH
OB Hospitalist
Morehouse School of Medicine
Atlanta, Georgia

Cherise Cokley, MD
OB Hospitalist
Community Hospital
Munster, Indiana

J’Leise Sosa, MD, MPH
ObGyn
Buffalo, New York

Recurrent episodic blood loss from normal menstruation is not expected to result in anemia. But without treatment, chronic heavy periods will progress through the stages of low iron stores to iron deficiency and then to anemia. When iron storage levels are low, the bone marrow’s blood cell factory cannot keep up with continued losses. Every patient with heavy menstrual bleeding (HMB) or prolonged menstrual episodes should be tested and treated for iron deficiency and anemia.^1,2

Particular attention should be paid to assessment of iron storage levels with serum ferritin, recognizing that low iron levels progress to anemia once the storage is depleted. Recovery from anemia is much slower in individuals with iron deficiency, so assessment for iron storage also should be included in preoperative assessments and following a diagnosis of acute blood loss anemia.

The mechanics of erythropoiesis, hemoglobin, and oxygen transport

Red blood cells (erythrocytes) have a short life cycle and require constant replacement. Erythrocytes are generated on demand in erythropoiesis by a hormonal signaling process, regardless of whether sufficient components are available.³ Hemoglobin, the main intracellular component of erythrocytes, is comprised of 4 globin chains, which each contain 1 iron atom bound to a heme molecule. After erythrocytes are assembled, they are sent out into circulation for approximately 120 days. A hemoglobin level measures the oxygen-carrying capacity of erythrocytes, and anemia is defined as hemoglobin less than 12 g/dL.

Unless erythrocytes are lost from bleeding, they are decommissioned—that is, the heme molecule is metabolized into bilirubin and excreted, and the iron atoms are recycled back to the bone marrow or to storage.⁴ Ferritin is the storage molecule that binds to iron, a glycoprotein with numerous subunits around a core that can contain about 4,000 iron atoms. Most ferritin is intracellular, but a small proportion is present in serum, where it can be measured.

Serum ferritin is a good marker for the iron supply in healthy individuals because it has high correlation to iron in the bone marrow and correlates to total intracellular storage unless there is inflammation, when mobilization to serum increases. The ferritin level at which the iron supply is deficient to meet demand, defined as iron deficiency, is hotly debated and ranges from less than 15 to 50 ng/mL in menstruating individuals, with higher thresholds based on onset of erythropoiesis signaling and the lower threshold being the World Health Organization recommendation.^5-7 When iron atoms are in short supply, erythrocytes still are generated but they have lower amounts of intracellular hemoglobin, which makes them thinner, smaller, and paler—and less effective at oxygen transport.

CASE Patient seeks treatment for HMB-associated symptoms

A 17-year-old patient presents with HMB, fatigue, and difficulty with concentration. She reports that her periods have been regular and lasting 7 days since menarche at age 13. While they are manageable, they seem to be getting heavier, soaking pads in 2 to 3 hours. The patient reports that she would like to start treatment for her progressively heavy bleeding and prefers lighter scheduled bleeding; she currently does not desire contraception. The patient has no family history of bleeding problems and self-reports no personal history of epistaxis or bleeding with tooth extraction or tonsillectomy. Laboratory tests confirm iron deficiency with a hemoglobin level of 12.5 g/dL (reference range, 12.0–17.5 g/dL) and a serum ferritin level of 8 ng/mL (reference range, 50–420 ng/mL). Results from a coagulopathy panel are normal, as are von Willebrand factor levels.

Untreated iron deficiency will progress to anemia

This patient has iron deficiency without anemia, which warrants significant attention in HMB because without treatment it eventually will progress to anemia. The prevalence of iron deficiency, which makes up half of all causes of anemia, is at least double that of iron deficiency anemia.³

Adult bodies usually contain about 3 to 4 g of iron, with two-thirds in erythrocytes as hemoglobin.⁸ Approximately 40 to 60 mg of iron is recycled daily, 1 to 2 mg/day is lost from sloughed cells and sweat, and at least 1 mg/day is lost during normal menstruation. These losses are balanced with gastrointestinal uptake of 1 to 2 mg/day until bleeding exceeds about 10 mL/day. In this 17-year-old patient, iron stores have likely been on a progressive decline since menarche.

For normally menstruating individuals to maintain iron homeostasis, the daily dietary iron requirement is 18 mg/day. Iron requirements also increase during periods of illness or inflammation due to hormonal signaling in the iron absorption and transport pathway, in athletes due to sweating, foot strike hemolysis and bruising, and during growth spurts.⁹

Continue to: Managing iron deficiency and anemia...

Management of iron deficiency and iron deficiency anemia in the setting of HMB includes:

• workup for the etiology of the abnormal uterine bleeding (TABLE)
• reducing the source of blood loss, and
• iron supplementation to correct the iron deficiency state.

In most cases, workup, reduction, and repletion can occur simultaneously. The goal is not always complete cessation of menstrual bleeding; even short-term therapy can allow time to replenish iron storage. Use a shared decision-making process to assess what is important to the patient, and provide information about relative amounts of bleeding cessation that can be expected with various therapies.¹⁰

Treatment options

Medical treatments to decrease menstrual iron losses are recommended prior to proceeding with surgical interventions.¹¹ Hormonal treatments are the most consistently recommended, with many guidelines citing the 52-mg levonorgestrel-releasing intrauterine device (LNG IUD) as first-line treatment due to its substantial reduction in the amount of bleeding, HMB treatment indication approved by the US Food and Drug Administration (FDA), and evidence of success in those with HMB.¹²

Any progestin or combined hormonal medication with estrogen and a progestin will result in an approximately 60% to 90% bleeding reduction, thus providing many effective options for blood loss while considering patient preferences for bleeding pattern, route of administration, and concomitant benefits. While only 1 oral product (estradiol valerate/dienogest) is FDA approved for managementof HMB, use of any of the commercially available contraceptive products will provide substantial benefit.^11,13

Nonhormonal options, such as antifibrinolytics and nonsteroidal anti-inflammatory drugs (NSAIDs), tend to be listed as second-line therapies or for those who want to avoid hormonal medications. Antifibrinolytics, such as tranexamic acid, require frequent dosing of large pills and result in approximately 40% blood loss reduction, but they are a very successful and well-tolerated method for those seeking on-demand therapy.¹⁴ NSAIDs may result in a slight bleeding reduction, but they are far less effective than other therapies.¹⁵ Antifibrinolytics have a theoretical risk of thrombosis and a contraindication to use with hormonal contraceptives; therefore, concomitant use with estrogen-containing medications is reserved for patients with refractory heavy bleeding or for heavy bleeding days during the hormone-free interval, when benefits likely outweigh potential risk.^16,17

Guidelines for medical management of acute HMB typically cite 3 small comparative studies with high-dose regimens of parenteral conjugated estrogen, combined ethinyl estradiol and progestin, or oral medroxyprogesterone acetate.^18,19 Dosing recommendations for the oral medications include a loading dose followed by a taper regimen that is poorly tolerated and for which there is no evidence of superior effectiveness over the standard dose.^20,21In most cases, initiation of the preferred long-term hormonal medication plan will reduce bleeding significantly within 2 to 3 days. Many clinicians who commonly treat acute HMB prescribe norethindrone acetate 5 mg daily (up to 3 times daily, if needed) for effective and safe menstrual suppression.²²

Iron replenishment: Dosing frequency, dietary iron, and multivitamins

Iron repletion is usually via the oral route unless surgery is imminent, anemia is severe, or the oral route is not tolerated or effective.²³ Oral iron has substantial adverse effects that limit tolerance, including nausea, epigastric pain, diarrhea, and constipation. Fortunately, evidence supports lower oral iron doses than previously used.⁴

Iron homeostasis is controlled by the peptide hormone hepcidin, produced by the liver, which controls mobilization of iron from the gut and spleen and aids iron absorption from the diet and supplements.²⁴ Hepcidin levels decrease in response to high circulating levels of iron, so the ideal iron repletion dose in iron-deficient nonanemic women was determined by assessing the dose response of hepcidin. Researchers compared iron 60 mg daily for 14 days versus every other day for 28 days and found that iron absorption was greater in the every-other-day group (21.8% vs 16.3%).²⁵They concluded that changing iron administration to 60 mg or more in a single dose every other day is most efficient in those with iron deficiency without anemia. Since study participants did not have anemia, research is pending on whether different strategies (such as daily dosing) are more effective for more severe cases. The bottom line is that conventional high-dose divided daily oral iron administration results in reduced iron bioavailability compared with alternate-day dosing.

Increasing dietary iron is insufficient to treat low iron storage, iron deficiency, and iron deficiency anemia. Likewise, multivitamins, which contain very little elemental iron, are not recommended for repletion. Any iron salt with 60 to 120 mg of elemental iron can be used (for examples, ferrous sulfate, ferrous gluconate).²⁵ Once ingested, stomach and pancreatic acids release elemental iron from its bound form. For that reason, absorption may be improved by administering iron at least 1 hour before a meal and avoiding antacids, including milk. Meat proteins and ascorbic acid help maintain the soluble ferrous form and also aid absorption. Tea, coffee, and tannins prevent absorption when polyphenol compounds form an insoluble complex with iron (see box at end of article). Gastrointestinal adverse effects can be minimized by decreasing the dose and taking after meals, although with reduced efficacy.

Intravenous iron treatment raises hemoglobin levels significantly faster than oral administration but is limited by cost and availability, so it is reserved for individuals with a hemoglobin level less than 9 g/dL, prior gastrointestinal or bariatric surgery, imminent surgery, and intolerance, poor adherence, or nonresponse to oral iron therapy. Several approved formulations are available, all with equivalent effectiveness and similar safety profiles. Lower-dose formulations (such as iron sucrose) may require several infusions, but higher-dose intravenous iron products (ferric carboxymaltose, low-molecular weight iron dextran, etc) have a stable carbohydrate shell that inhibits free iron release and improves safety, allowing a single administration.²⁶

Common adverse effects of intravenous iron treatment include a metallic taste and headache during administration. More serious adverse effects, such as hypotension, arthralgia, malaise, and nausea, are usually self-limited. With mild infusion reactions (1 in 200), the infusion can be stopped until symptoms improve and can be resumed at a slower rate.²⁷

Continue to: The role of blood transfusion...

The role of blood transfusion

Blood transfusion is expensive and potentially hazardous, so its use is limited to treatment of acute blood loss or severe anemia.

A one-time red blood cell transfusion does not impact diagnostic criteria to assess for iron deficiency with ferritin, and it does not improve underlying iron deficiency.²⁸Patients with acute blood loss anemia superimposed on chronic blood loss should be screened and treated for iron deficiency even after receiving a transfusion.

Since ferritin levels can rise significantly as an acute phase reactant, even following a hemorrhage, iron deficiency during inflammation is defined as ferritin less than 70 ng/mL.

The potential for iron overload

Since iron is never metabolized or excreted, it is possible to have iron overload following accidental overdose, transfusion dependency, and disorders of iron transport, such as hemochromatosis and thalassemia.

While a low ferritin level always indicates iron deficiency, high ferritin levels can be an acute phase reactant. Ferritin levels greater than 150 ng/mL in healthy menstruating individuals and greater than 500 ng/mL in unhealthy individuals should raise concern for excess iron and should prompt discontinuation of iron intake or workup for conditions at risk for overload.⁵

Oral iron supplements should be stored away from small children, who are at particular risk of toxicity.

How long to treat?

Treatment duration depends on the individual’s degree of iron deficiency, whether anemia is present, and the amount of ongoing blood loss. The main treatment goal is normalization and maintenance of serum ferritin.

Successful treatment should be confirmed with a complete blood count and ferritin level. Hemoglobin levels improve 2 g/dL after 3 weeks of oral iron therapy, but repletion may take 4 to 6 months.^23,29 The American College of Obstetricians and Gynecologists recommends 3 to 6 months of continued iron therapy after resolution of HMB.¹⁹

In a comparative study of treatment for HMB with the 52-mg LNG IUD versus hysterectomy, hemoglobin levels increased in both treatment groups but stayed lower in those with initial anemia.⁸ Ferritin levels normalized only after 5 years and were still lower in individuals with initial anemia.

Increase in hemoglobin is faster after intravenous iron administration but is equivalent to oral therapy by 12 weeks. If management to reduce menstrual losses is discontinued, periodic or maintenance iron repletion will be necessary.

CASE Management plan initiated

This 17-year-old patient with iron deficiency resulting from HMB requests management to reduce menstrual iron losses with a preference for predictable menses. We have already completed a basic workup, which could also include assessment for hypermobility with a Beighton score, as connective tissue disorders also are associated with HMB.³⁰ We discuss the options of cyclic hormonal therapy, antifibrinolytic treatment, and an LNG IUD. The patient is concerned about adherence and wants to avoid unscheduled bleeding, so she opts for a trial of tranexamic acid 1,300 mg 3 times daily for 5 days during menses. This regimen results in a 50% reduction in bleeding amount, which the patient finds satisfactory. Iron repletion with oral ferrous sulfate 325 mg (containing 65 mg of elemental iron) is administered on alternating days with vitamin C taken 1 hour prior to dinner. Repeat laboratory test results at 3 weeks show improvement to a hemoglobin level of 14.2 g/dL and a ferritin level of 12 ng/mL. By 3 months, her ferritin levels are greater than 30 ng/mL and oral iron is administered only during menses.

Summing up

Chronic HMB results in a progressive net loss of iron and eventual anemia. Screening with complete blood count and ferritin and early treatment of low iron storage when ferritin is less than 30 ng/mL will help avoid symptoms. Any amount of reduction of menstrual blood loss can be beneficial, allowing a variety of effective hormonal and nonhormonal treatment options. ●

Recurrent episodic blood loss from normal menstruation is not expected to result in anemia. But without treatment, chronic heavy periods will progress through the stages of low iron stores to iron deficiency and then to anemia. When iron storage levels are low, the bone marrow’s blood cell factory cannot keep up with continued losses. Every patient with heavy menstrual bleeding (HMB) or prolonged menstrual episodes should be tested and treated for iron deficiency and anemia.^1,2

Particular attention should be paid to assessment of iron storage levels with serum ferritin, recognizing that low iron levels progress to anemia once the storage is depleted. Recovery from anemia is much slower in individuals with iron deficiency, so assessment for iron storage also should be included in preoperative assessments and following a diagnosis of acute blood loss anemia.

The mechanics of erythropoiesis, hemoglobin, and oxygen transport

Red blood cells (erythrocytes) have a short life cycle and require constant replacement. Erythrocytes are generated on demand in erythropoiesis by a hormonal signaling process, regardless of whether sufficient components are available.³ Hemoglobin, the main intracellular component of erythrocytes, is comprised of 4 globin chains, which each contain 1 iron atom bound to a heme molecule. After erythrocytes are assembled, they are sent out into circulation for approximately 120 days. A hemoglobin level measures the oxygen-carrying capacity of erythrocytes, and anemia is defined as hemoglobin less than 12 g/dL.

Unless erythrocytes are lost from bleeding, they are decommissioned—that is, the heme molecule is metabolized into bilirubin and excreted, and the iron atoms are recycled back to the bone marrow or to storage.⁴ Ferritin is the storage molecule that binds to iron, a glycoprotein with numerous subunits around a core that can contain about 4,000 iron atoms. Most ferritin is intracellular, but a small proportion is present in serum, where it can be measured.

Serum ferritin is a good marker for the iron supply in healthy individuals because it has high correlation to iron in the bone marrow and correlates to total intracellular storage unless there is inflammation, when mobilization to serum increases. The ferritin level at which the iron supply is deficient to meet demand, defined as iron deficiency, is hotly debated and ranges from less than 15 to 50 ng/mL in menstruating individuals, with higher thresholds based on onset of erythropoiesis signaling and the lower threshold being the World Health Organization recommendation.^5-7 When iron atoms are in short supply, erythrocytes still are generated but they have lower amounts of intracellular hemoglobin, which makes them thinner, smaller, and paler—and less effective at oxygen transport.

CASE Patient seeks treatment for HMB-associated symptoms

A 17-year-old patient presents with HMB, fatigue, and difficulty with concentration. She reports that her periods have been regular and lasting 7 days since menarche at age 13. While they are manageable, they seem to be getting heavier, soaking pads in 2 to 3 hours. The patient reports that she would like to start treatment for her progressively heavy bleeding and prefers lighter scheduled bleeding; she currently does not desire contraception. The patient has no family history of bleeding problems and self-reports no personal history of epistaxis or bleeding with tooth extraction or tonsillectomy. Laboratory tests confirm iron deficiency with a hemoglobin level of 12.5 g/dL (reference range, 12.0–17.5 g/dL) and a serum ferritin level of 8 ng/mL (reference range, 50–420 ng/mL). Results from a coagulopathy panel are normal, as are von Willebrand factor levels.

Untreated iron deficiency will progress to anemia

This patient has iron deficiency without anemia, which warrants significant attention in HMB because without treatment it eventually will progress to anemia. The prevalence of iron deficiency, which makes up half of all causes of anemia, is at least double that of iron deficiency anemia.³

Adult bodies usually contain about 3 to 4 g of iron, with two-thirds in erythrocytes as hemoglobin.⁸ Approximately 40 to 60 mg of iron is recycled daily, 1 to 2 mg/day is lost from sloughed cells and sweat, and at least 1 mg/day is lost during normal menstruation. These losses are balanced with gastrointestinal uptake of 1 to 2 mg/day until bleeding exceeds about 10 mL/day. In this 17-year-old patient, iron stores have likely been on a progressive decline since menarche.

For normally menstruating individuals to maintain iron homeostasis, the daily dietary iron requirement is 18 mg/day. Iron requirements also increase during periods of illness or inflammation due to hormonal signaling in the iron absorption and transport pathway, in athletes due to sweating, foot strike hemolysis and bruising, and during growth spurts.⁹

Continue to: Managing iron deficiency and anemia...

Management of iron deficiency and iron deficiency anemia in the setting of HMB includes:

• workup for the etiology of the abnormal uterine bleeding (TABLE)
• reducing the source of blood loss, and
• iron supplementation to correct the iron deficiency state.

In most cases, workup, reduction, and repletion can occur simultaneously. The goal is not always complete cessation of menstrual bleeding; even short-term therapy can allow time to replenish iron storage. Use a shared decision-making process to assess what is important to the patient, and provide information about relative amounts of bleeding cessation that can be expected with various therapies.¹⁰

Treatment options

Medical treatments to decrease menstrual iron losses are recommended prior to proceeding with surgical interventions.¹¹ Hormonal treatments are the most consistently recommended, with many guidelines citing the 52-mg levonorgestrel-releasing intrauterine device (LNG IUD) as first-line treatment due to its substantial reduction in the amount of bleeding, HMB treatment indication approved by the US Food and Drug Administration (FDA), and evidence of success in those with HMB.¹²

Any progestin or combined hormonal medication with estrogen and a progestin will result in an approximately 60% to 90% bleeding reduction, thus providing many effective options for blood loss while considering patient preferences for bleeding pattern, route of administration, and concomitant benefits. While only 1 oral product (estradiol valerate/dienogest) is FDA approved for managementof HMB, use of any of the commercially available contraceptive products will provide substantial benefit.^11,13

Nonhormonal options, such as antifibrinolytics and nonsteroidal anti-inflammatory drugs (NSAIDs), tend to be listed as second-line therapies or for those who want to avoid hormonal medications. Antifibrinolytics, such as tranexamic acid, require frequent dosing of large pills and result in approximately 40% blood loss reduction, but they are a very successful and well-tolerated method for those seeking on-demand therapy.¹⁴ NSAIDs may result in a slight bleeding reduction, but they are far less effective than other therapies.¹⁵ Antifibrinolytics have a theoretical risk of thrombosis and a contraindication to use with hormonal contraceptives; therefore, concomitant use with estrogen-containing medications is reserved for patients with refractory heavy bleeding or for heavy bleeding days during the hormone-free interval, when benefits likely outweigh potential risk.^16,17

Guidelines for medical management of acute HMB typically cite 3 small comparative studies with high-dose regimens of parenteral conjugated estrogen, combined ethinyl estradiol and progestin, or oral medroxyprogesterone acetate.^18,19 Dosing recommendations for the oral medications include a loading dose followed by a taper regimen that is poorly tolerated and for which there is no evidence of superior effectiveness over the standard dose.^20,21In most cases, initiation of the preferred long-term hormonal medication plan will reduce bleeding significantly within 2 to 3 days. Many clinicians who commonly treat acute HMB prescribe norethindrone acetate 5 mg daily (up to 3 times daily, if needed) for effective and safe menstrual suppression.²²

Iron replenishment: Dosing frequency, dietary iron, and multivitamins

Iron repletion is usually via the oral route unless surgery is imminent, anemia is severe, or the oral route is not tolerated or effective.²³ Oral iron has substantial adverse effects that limit tolerance, including nausea, epigastric pain, diarrhea, and constipation. Fortunately, evidence supports lower oral iron doses than previously used.⁴

Iron homeostasis is controlled by the peptide hormone hepcidin, produced by the liver, which controls mobilization of iron from the gut and spleen and aids iron absorption from the diet and supplements.²⁴ Hepcidin levels decrease in response to high circulating levels of iron, so the ideal iron repletion dose in iron-deficient nonanemic women was determined by assessing the dose response of hepcidin. Researchers compared iron 60 mg daily for 14 days versus every other day for 28 days and found that iron absorption was greater in the every-other-day group (21.8% vs 16.3%).²⁵They concluded that changing iron administration to 60 mg or more in a single dose every other day is most efficient in those with iron deficiency without anemia. Since study participants did not have anemia, research is pending on whether different strategies (such as daily dosing) are more effective for more severe cases. The bottom line is that conventional high-dose divided daily oral iron administration results in reduced iron bioavailability compared with alternate-day dosing.

Increasing dietary iron is insufficient to treat low iron storage, iron deficiency, and iron deficiency anemia. Likewise, multivitamins, which contain very little elemental iron, are not recommended for repletion. Any iron salt with 60 to 120 mg of elemental iron can be used (for examples, ferrous sulfate, ferrous gluconate).²⁵ Once ingested, stomach and pancreatic acids release elemental iron from its bound form. For that reason, absorption may be improved by administering iron at least 1 hour before a meal and avoiding antacids, including milk. Meat proteins and ascorbic acid help maintain the soluble ferrous form and also aid absorption. Tea, coffee, and tannins prevent absorption when polyphenol compounds form an insoluble complex with iron (see box at end of article). Gastrointestinal adverse effects can be minimized by decreasing the dose and taking after meals, although with reduced efficacy.

Intravenous iron treatment raises hemoglobin levels significantly faster than oral administration but is limited by cost and availability, so it is reserved for individuals with a hemoglobin level less than 9 g/dL, prior gastrointestinal or bariatric surgery, imminent surgery, and intolerance, poor adherence, or nonresponse to oral iron therapy. Several approved formulations are available, all with equivalent effectiveness and similar safety profiles. Lower-dose formulations (such as iron sucrose) may require several infusions, but higher-dose intravenous iron products (ferric carboxymaltose, low-molecular weight iron dextran, etc) have a stable carbohydrate shell that inhibits free iron release and improves safety, allowing a single administration.²⁶

Common adverse effects of intravenous iron treatment include a metallic taste and headache during administration. More serious adverse effects, such as hypotension, arthralgia, malaise, and nausea, are usually self-limited. With mild infusion reactions (1 in 200), the infusion can be stopped until symptoms improve and can be resumed at a slower rate.²⁷

Continue to: The role of blood transfusion...

The role of blood transfusion

Blood transfusion is expensive and potentially hazardous, so its use is limited to treatment of acute blood loss or severe anemia.

A one-time red blood cell transfusion does not impact diagnostic criteria to assess for iron deficiency with ferritin, and it does not improve underlying iron deficiency.²⁸Patients with acute blood loss anemia superimposed on chronic blood loss should be screened and treated for iron deficiency even after receiving a transfusion.

Since ferritin levels can rise significantly as an acute phase reactant, even following a hemorrhage, iron deficiency during inflammation is defined as ferritin less than 70 ng/mL.

The potential for iron overload

Since iron is never metabolized or excreted, it is possible to have iron overload following accidental overdose, transfusion dependency, and disorders of iron transport, such as hemochromatosis and thalassemia.

While a low ferritin level always indicates iron deficiency, high ferritin levels can be an acute phase reactant. Ferritin levels greater than 150 ng/mL in healthy menstruating individuals and greater than 500 ng/mL in unhealthy individuals should raise concern for excess iron and should prompt discontinuation of iron intake or workup for conditions at risk for overload.⁵

Oral iron supplements should be stored away from small children, who are at particular risk of toxicity.

How long to treat?

Treatment duration depends on the individual’s degree of iron deficiency, whether anemia is present, and the amount of ongoing blood loss. The main treatment goal is normalization and maintenance of serum ferritin.

Successful treatment should be confirmed with a complete blood count and ferritin level. Hemoglobin levels improve 2 g/dL after 3 weeks of oral iron therapy, but repletion may take 4 to 6 months.^23,29 The American College of Obstetricians and Gynecologists recommends 3 to 6 months of continued iron therapy after resolution of HMB.¹⁹

In a comparative study of treatment for HMB with the 52-mg LNG IUD versus hysterectomy, hemoglobin levels increased in both treatment groups but stayed lower in those with initial anemia.⁸ Ferritin levels normalized only after 5 years and were still lower in individuals with initial anemia.

Increase in hemoglobin is faster after intravenous iron administration but is equivalent to oral therapy by 12 weeks. If management to reduce menstrual losses is discontinued, periodic or maintenance iron repletion will be necessary.

CASE Management plan initiated

This 17-year-old patient with iron deficiency resulting from HMB requests management to reduce menstrual iron losses with a preference for predictable menses. We have already completed a basic workup, which could also include assessment for hypermobility with a Beighton score, as connective tissue disorders also are associated with HMB.³⁰ We discuss the options of cyclic hormonal therapy, antifibrinolytic treatment, and an LNG IUD. The patient is concerned about adherence and wants to avoid unscheduled bleeding, so she opts for a trial of tranexamic acid 1,300 mg 3 times daily for 5 days during menses. This regimen results in a 50% reduction in bleeding amount, which the patient finds satisfactory. Iron repletion with oral ferrous sulfate 325 mg (containing 65 mg of elemental iron) is administered on alternating days with vitamin C taken 1 hour prior to dinner. Repeat laboratory test results at 3 weeks show improvement to a hemoglobin level of 14.2 g/dL and a ferritin level of 12 ng/mL. By 3 months, her ferritin levels are greater than 30 ng/mL and oral iron is administered only during menses.

Summing up

Chronic HMB results in a progressive net loss of iron and eventual anemia. Screening with complete blood count and ferritin and early treatment of low iron storage when ferritin is less than 30 ng/mL will help avoid symptoms. Any amount of reduction of menstrual blood loss can be beneficial, allowing a variety of effective hormonal and nonhormonal treatment options. ●

Recurrent episodic blood loss from normal menstruation is not expected to result in anemia. But without treatment, chronic heavy periods will progress through the stages of low iron stores to iron deficiency and then to anemia. When iron storage levels are low, the bone marrow’s blood cell factory cannot keep up with continued losses. Every patient with heavy menstrual bleeding (HMB) or prolonged menstrual episodes should be tested and treated for iron deficiency and anemia.^1,2

Particular attention should be paid to assessment of iron storage levels with serum ferritin, recognizing that low iron levels progress to anemia once the storage is depleted. Recovery from anemia is much slower in individuals with iron deficiency, so assessment for iron storage also should be included in preoperative assessments and following a diagnosis of acute blood loss anemia.

The mechanics of erythropoiesis, hemoglobin, and oxygen transport

Red blood cells (erythrocytes) have a short life cycle and require constant replacement. Erythrocytes are generated on demand in erythropoiesis by a hormonal signaling process, regardless of whether sufficient components are available.³ Hemoglobin, the main intracellular component of erythrocytes, is comprised of 4 globin chains, which each contain 1 iron atom bound to a heme molecule. After erythrocytes are assembled, they are sent out into circulation for approximately 120 days. A hemoglobin level measures the oxygen-carrying capacity of erythrocytes, and anemia is defined as hemoglobin less than 12 g/dL.

Unless erythrocytes are lost from bleeding, they are decommissioned—that is, the heme molecule is metabolized into bilirubin and excreted, and the iron atoms are recycled back to the bone marrow or to storage.⁴ Ferritin is the storage molecule that binds to iron, a glycoprotein with numerous subunits around a core that can contain about 4,000 iron atoms. Most ferritin is intracellular, but a small proportion is present in serum, where it can be measured.

Serum ferritin is a good marker for the iron supply in healthy individuals because it has high correlation to iron in the bone marrow and correlates to total intracellular storage unless there is inflammation, when mobilization to serum increases. The ferritin level at which the iron supply is deficient to meet demand, defined as iron deficiency, is hotly debated and ranges from less than 15 to 50 ng/mL in menstruating individuals, with higher thresholds based on onset of erythropoiesis signaling and the lower threshold being the World Health Organization recommendation.^5-7 When iron atoms are in short supply, erythrocytes still are generated but they have lower amounts of intracellular hemoglobin, which makes them thinner, smaller, and paler—and less effective at oxygen transport.

CASE Patient seeks treatment for HMB-associated symptoms

A 17-year-old patient presents with HMB, fatigue, and difficulty with concentration. She reports that her periods have been regular and lasting 7 days since menarche at age 13. While they are manageable, they seem to be getting heavier, soaking pads in 2 to 3 hours. The patient reports that she would like to start treatment for her progressively heavy bleeding and prefers lighter scheduled bleeding; she currently does not desire contraception. The patient has no family history of bleeding problems and self-reports no personal history of epistaxis or bleeding with tooth extraction or tonsillectomy. Laboratory tests confirm iron deficiency with a hemoglobin level of 12.5 g/dL (reference range, 12.0–17.5 g/dL) and a serum ferritin level of 8 ng/mL (reference range, 50–420 ng/mL). Results from a coagulopathy panel are normal, as are von Willebrand factor levels.

Untreated iron deficiency will progress to anemia

This patient has iron deficiency without anemia, which warrants significant attention in HMB because without treatment it eventually will progress to anemia. The prevalence of iron deficiency, which makes up half of all causes of anemia, is at least double that of iron deficiency anemia.³

Adult bodies usually contain about 3 to 4 g of iron, with two-thirds in erythrocytes as hemoglobin.⁸ Approximately 40 to 60 mg of iron is recycled daily, 1 to 2 mg/day is lost from sloughed cells and sweat, and at least 1 mg/day is lost during normal menstruation. These losses are balanced with gastrointestinal uptake of 1 to 2 mg/day until bleeding exceeds about 10 mL/day. In this 17-year-old patient, iron stores have likely been on a progressive decline since menarche.

For normally menstruating individuals to maintain iron homeostasis, the daily dietary iron requirement is 18 mg/day. Iron requirements also increase during periods of illness or inflammation due to hormonal signaling in the iron absorption and transport pathway, in athletes due to sweating, foot strike hemolysis and bruising, and during growth spurts.⁹

Continue to: Managing iron deficiency and anemia...

Management of iron deficiency and iron deficiency anemia in the setting of HMB includes:

• workup for the etiology of the abnormal uterine bleeding (TABLE)
• reducing the source of blood loss, and
• iron supplementation to correct the iron deficiency state.

In most cases, workup, reduction, and repletion can occur simultaneously. The goal is not always complete cessation of menstrual bleeding; even short-term therapy can allow time to replenish iron storage. Use a shared decision-making process to assess what is important to the patient, and provide information about relative amounts of bleeding cessation that can be expected with various therapies.¹⁰

Treatment options

Medical treatments to decrease menstrual iron losses are recommended prior to proceeding with surgical interventions.¹¹ Hormonal treatments are the most consistently recommended, with many guidelines citing the 52-mg levonorgestrel-releasing intrauterine device (LNG IUD) as first-line treatment due to its substantial reduction in the amount of bleeding, HMB treatment indication approved by the US Food and Drug Administration (FDA), and evidence of success in those with HMB.¹²

Any progestin or combined hormonal medication with estrogen and a progestin will result in an approximately 60% to 90% bleeding reduction, thus providing many effective options for blood loss while considering patient preferences for bleeding pattern, route of administration, and concomitant benefits. While only 1 oral product (estradiol valerate/dienogest) is FDA approved for managementof HMB, use of any of the commercially available contraceptive products will provide substantial benefit.^11,13

Nonhormonal options, such as antifibrinolytics and nonsteroidal anti-inflammatory drugs (NSAIDs), tend to be listed as second-line therapies or for those who want to avoid hormonal medications. Antifibrinolytics, such as tranexamic acid, require frequent dosing of large pills and result in approximately 40% blood loss reduction, but they are a very successful and well-tolerated method for those seeking on-demand therapy.¹⁴ NSAIDs may result in a slight bleeding reduction, but they are far less effective than other therapies.¹⁵ Antifibrinolytics have a theoretical risk of thrombosis and a contraindication to use with hormonal contraceptives; therefore, concomitant use with estrogen-containing medications is reserved for patients with refractory heavy bleeding or for heavy bleeding days during the hormone-free interval, when benefits likely outweigh potential risk.^16,17

Guidelines for medical management of acute HMB typically cite 3 small comparative studies with high-dose regimens of parenteral conjugated estrogen, combined ethinyl estradiol and progestin, or oral medroxyprogesterone acetate.^18,19 Dosing recommendations for the oral medications include a loading dose followed by a taper regimen that is poorly tolerated and for which there is no evidence of superior effectiveness over the standard dose.^20,21In most cases, initiation of the preferred long-term hormonal medication plan will reduce bleeding significantly within 2 to 3 days. Many clinicians who commonly treat acute HMB prescribe norethindrone acetate 5 mg daily (up to 3 times daily, if needed) for effective and safe menstrual suppression.²²

Iron replenishment: Dosing frequency, dietary iron, and multivitamins

Iron repletion is usually via the oral route unless surgery is imminent, anemia is severe, or the oral route is not tolerated or effective.²³ Oral iron has substantial adverse effects that limit tolerance, including nausea, epigastric pain, diarrhea, and constipation. Fortunately, evidence supports lower oral iron doses than previously used.⁴

Iron homeostasis is controlled by the peptide hormone hepcidin, produced by the liver, which controls mobilization of iron from the gut and spleen and aids iron absorption from the diet and supplements.²⁴ Hepcidin levels decrease in response to high circulating levels of iron, so the ideal iron repletion dose in iron-deficient nonanemic women was determined by assessing the dose response of hepcidin. Researchers compared iron 60 mg daily for 14 days versus every other day for 28 days and found that iron absorption was greater in the every-other-day group (21.8% vs 16.3%).²⁵They concluded that changing iron administration to 60 mg or more in a single dose every other day is most efficient in those with iron deficiency without anemia. Since study participants did not have anemia, research is pending on whether different strategies (such as daily dosing) are more effective for more severe cases. The bottom line is that conventional high-dose divided daily oral iron administration results in reduced iron bioavailability compared with alternate-day dosing.

Increasing dietary iron is insufficient to treat low iron storage, iron deficiency, and iron deficiency anemia. Likewise, multivitamins, which contain very little elemental iron, are not recommended for repletion. Any iron salt with 60 to 120 mg of elemental iron can be used (for examples, ferrous sulfate, ferrous gluconate).²⁵ Once ingested, stomach and pancreatic acids release elemental iron from its bound form. For that reason, absorption may be improved by administering iron at least 1 hour before a meal and avoiding antacids, including milk. Meat proteins and ascorbic acid help maintain the soluble ferrous form and also aid absorption. Tea, coffee, and tannins prevent absorption when polyphenol compounds form an insoluble complex with iron (see box at end of article). Gastrointestinal adverse effects can be minimized by decreasing the dose and taking after meals, although with reduced efficacy.

Intravenous iron treatment raises hemoglobin levels significantly faster than oral administration but is limited by cost and availability, so it is reserved for individuals with a hemoglobin level less than 9 g/dL, prior gastrointestinal or bariatric surgery, imminent surgery, and intolerance, poor adherence, or nonresponse to oral iron therapy. Several approved formulations are available, all with equivalent effectiveness and similar safety profiles. Lower-dose formulations (such as iron sucrose) may require several infusions, but higher-dose intravenous iron products (ferric carboxymaltose, low-molecular weight iron dextran, etc) have a stable carbohydrate shell that inhibits free iron release and improves safety, allowing a single administration.²⁶

Common adverse effects of intravenous iron treatment include a metallic taste and headache during administration. More serious adverse effects, such as hypotension, arthralgia, malaise, and nausea, are usually self-limited. With mild infusion reactions (1 in 200), the infusion can be stopped until symptoms improve and can be resumed at a slower rate.²⁷

Continue to: The role of blood transfusion...

The role of blood transfusion

Blood transfusion is expensive and potentially hazardous, so its use is limited to treatment of acute blood loss or severe anemia.

A one-time red blood cell transfusion does not impact diagnostic criteria to assess for iron deficiency with ferritin, and it does not improve underlying iron deficiency.²⁸Patients with acute blood loss anemia superimposed on chronic blood loss should be screened and treated for iron deficiency even after receiving a transfusion.

Since ferritin levels can rise significantly as an acute phase reactant, even following a hemorrhage, iron deficiency during inflammation is defined as ferritin less than 70 ng/mL.

The potential for iron overload

Since iron is never metabolized or excreted, it is possible to have iron overload following accidental overdose, transfusion dependency, and disorders of iron transport, such as hemochromatosis and thalassemia.

While a low ferritin level always indicates iron deficiency, high ferritin levels can be an acute phase reactant. Ferritin levels greater than 150 ng/mL in healthy menstruating individuals and greater than 500 ng/mL in unhealthy individuals should raise concern for excess iron and should prompt discontinuation of iron intake or workup for conditions at risk for overload.⁵

Oral iron supplements should be stored away from small children, who are at particular risk of toxicity.

How long to treat?

Treatment duration depends on the individual’s degree of iron deficiency, whether anemia is present, and the amount of ongoing blood loss. The main treatment goal is normalization and maintenance of serum ferritin.

Successful treatment should be confirmed with a complete blood count and ferritin level. Hemoglobin levels improve 2 g/dL after 3 weeks of oral iron therapy, but repletion may take 4 to 6 months.^23,29 The American College of Obstetricians and Gynecologists recommends 3 to 6 months of continued iron therapy after resolution of HMB.¹⁹

In a comparative study of treatment for HMB with the 52-mg LNG IUD versus hysterectomy, hemoglobin levels increased in both treatment groups but stayed lower in those with initial anemia.⁸ Ferritin levels normalized only after 5 years and were still lower in individuals with initial anemia.

Increase in hemoglobin is faster after intravenous iron administration but is equivalent to oral therapy by 12 weeks. If management to reduce menstrual losses is discontinued, periodic or maintenance iron repletion will be necessary.

CASE Management plan initiated

This 17-year-old patient with iron deficiency resulting from HMB requests management to reduce menstrual iron losses with a preference for predictable menses. We have already completed a basic workup, which could also include assessment for hypermobility with a Beighton score, as connective tissue disorders also are associated with HMB.³⁰ We discuss the options of cyclic hormonal therapy, antifibrinolytic treatment, and an LNG IUD. The patient is concerned about adherence and wants to avoid unscheduled bleeding, so she opts for a trial of tranexamic acid 1,300 mg 3 times daily for 5 days during menses. This regimen results in a 50% reduction in bleeding amount, which the patient finds satisfactory. Iron repletion with oral ferrous sulfate 325 mg (containing 65 mg of elemental iron) is administered on alternating days with vitamin C taken 1 hour prior to dinner. Repeat laboratory test results at 3 weeks show improvement to a hemoglobin level of 14.2 g/dL and a ferritin level of 12 ng/mL. By 3 months, her ferritin levels are greater than 30 ng/mL and oral iron is administered only during menses.

Summing up

Chronic HMB results in a progressive net loss of iron and eventual anemia. Screening with complete blood count and ferritin and early treatment of low iron storage when ferritin is less than 30 ng/mL will help avoid symptoms. Any amount of reduction of menstrual blood loss can be beneficial, allowing a variety of effective hormonal and nonhormonal treatment options. ●

Febrile neutropenia (FN) is a life-threatening oncologic emergency requiring timely evaluation and treatment. Chemotherapy-induced neutropenia is a major risk for life-threatening infection, and fever may be the only sign.^1,2 Unrecognized fever can progress to sepsis and may result in increased morbidity and mortality. FN is defined as the presence of fever with a single temperature of  ≥ 38.3 °C or a sustained temperature > 38 °C sustained over 1 hour with an absolute neutrophil count (ANC) of < 500 cells/mm³ or < 1000 cells/mm³ and expected to decrease to < 500 within 48 hours.^2,3 It is critical to quickly identify these patients on presentation to the emergency department (ED) and take appropriate steps to initiate treatment as soon as possible. To streamline care, the American Society of Clinical Oncology (ASCO) recommends that laboratory assessments be initiated within 15 minutes of triage and empiric antibiotic therapy be administered within 1 hour.²

In alignment with the Infectious Disease Society of America (IDSA) guidelines, the National Comprehensive Cancer Network (NCCN) highlights the importance of the initial assessment of fever and neutropenia and presents available treatment options for both inpatient and outpatient management of FN.¹ Once patients are identified, the appropriate laboratory tests and physical assessments should be initiated immediately. These tests include a complete blood count with differential, complete metabolic panel (CMP), and blood cultures from 2 separate IV sites.^1-3 The guidelines offer additional suggestions for cultures and radiographic assessments that may be completed based on clinical presentation.

Several available studies provide insight into methods of protocol creation and possible barriers to timely management. Previous research showed that an FN protocol for pediatric oncology patients aimed at antibiotic administration within 1 hour showed significant improvement from 35.0% to 55.4% of patients being treated on time.^3,4 Prescribers became more comfortable in using the protocol, and timing improved as the study progressed. Barriers noted were inconsistent ED triage, rotating ED staff, and limited understanding of the protocol.³ Yoshida and colleagues worked with the same population. Over the course of 1 year, 60% of patients were receiving antibiotics within 1 hour. The mean time decreased from 83 to 65 minutes, which the study investigators noted would continue to decrease with increased protocol comfort and use.⁵ Mattison and colleagues used nursing staff to identify patients with FN and begin antibiotic treatment. On triage, nurses took note of a temperature of > 38 °C or a sepsislike clinical picture that initiated their antibiotic proforma.^4,6 This resulted in 48.1% of patients receiving antibiotics within 15 minutes and 63.3% overall within 30 minutes of arrival.⁵ Other barriers to consider are ED crowding and the admission of higher acuity patients, which may delay the treatment of patients with FN.

The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana is a level 1A facility serving about 62,000 veterans annually and more than 13,000 unique veterans visiting the ED. RLRVAMC ED staff rotate often so the creation of a process will facilitate appropriate treatment as quickly as possible. The purpose of this protocol was to improve the mean time from triage to administration of antibiotics for patients with FN presenting to the ED.

Implementation

To quantify the perceived delay in antibiotic prescribing, a pre- and postprotocol retrospective chart review of patients who presented with FN to the RLRVAMC ED was conducted. Patients were identified through the electronic health record (EHR) based on 3 criteria: recorded/reported fever as defined above, ANC < 1000 cells/mm³, and administration of cancer treatment (IV and oral) within 4 weeks. The data collected in the postimplementation phase were identical to the pre-implementation phase. This included timing of blood cultures, choice/appropriateness of antibiotics based on guidelines, and length of admission. The pre-implementation period started on August 1, 2018, and ended on August 1, 2019, to allow for an adequate pre-implementation sample size. The protocol was then implemented on October 1, 2019, and data collection for the postimplementation phase began on October 1,2019, and ended on October 1, 2020.

The protocol was accompanied by EHR order sets initiated by both nurses and health care practitioners (HCPs), including physicians, nurse practitioners, and physician assistants. The nursing order set consisted of vitals and appropriate laboratory monitoring, and the practitioner order set housed medication orders and additional clinical monitoring for more patient-specific scenarios. On identification of at-risk patients, the nursing staff could initiate the neutropenic fever protocol without consulting an HCP. The patient was then assigned a higher acuity rank, and the HCP was tasked with seeing the patient immediately. In conjunction with a complete physical assessment, the HCP ordered appropriate antibiotics through the designated order set to streamline antibiotic selection. Antibiotic options included cefepime or piperacillin-tazobactam, and vancomycin when clinically indicated. Alternatives for patients allergic to penicillin also were available. The protocol intended to streamline workup and antibiotic selection but was not designed as a substitute for solid clinical decision making and complete assessment on behalf of the HCP; therefore, additional workup may have been necessary and documented in the EHR.

Findings

This patient population comprised 17 patients pre-implementation and 12 patients postimplementation, most of whom had solid tumor malignancies (88.2% and 83.3%, respectively) receiving platinum, taxane, or antimetabolite-based chemotherapy. In the pre-implementation group, most patients (70.5%) coming through the ED were treated with palliative intent. Only 25% of these received any prophylactic granulocyte-colony stimulating factor (G-CSF) based on risk for FN. The mean time from triage to the first dose of antibiotics decreased from 3.3 hours before protocol implementation to 2.3 hours after. Only 6% in the pre-implementation group compared with 17% in the postimplementation group received the first dose of antibiotics within the recommended 1-hour interval from triage. The most common antibiotics administered were cefepime and vancomycin. Eleven patients in each group (65% and 92%, respectively) were admitted to the inpatient service for further care, with 10 and 8 patients, respectively, experiencing a hospitalization > 72 hours. Of note, 41% of patients died pre-implementation vs 17% postimplementation.

Interpretation

The goal of this protocol was to optimize ED care of patients presenting with FN to better align with guideline-recommended time lines and antibiotics. The mean time from triage to administration of antibiotics decreased by 1.0 hour from the pre- to postimplementation phase, similar to the study by Mattison and colleagues.³ When removing an outlier from the postimplementation group, the mean time from triage to first dose further decreased to 1.8 hours. The percentage of patients receiving antibiotics within 1 hour of triage nearly tripled from 6% to 17%. Additionally, the percentage of patients empirically treated with appropriate antibiotics consistent with NCCN/ASCO/IDSA guidelines increased from 65% to 83%. Although goals for the optimization of care have not yet been reached, this protocol is the first step in the right direction.

Limitations

Several limitations and concerns arise when implementing a new protocol or workflow process. Overall, these limitations may contribute to delays, such as the willingness of team members to use an unfamiliar protocol or issues locating a new protocol. The nursing staff is challenged to triage patients quickly, which may add to an already busy environment. Frequent physician turnover may require more frequent education sessions. Also, a lag time between implementation and using the protocol may result in decreased protocol use during the designated postimplementation data collection phase.

On review, ED staff were excited to find a protocol that streamlined decision making and increased awareness for patients at risk. The COVID-19 pandemic may have been a confounder for the postimplementation phase. Data may have been skewed as some patients might have elected to stay at home to avoid potential COVID-19 exposure in the ED. Additionally, increased ED use by patients with COVID-19 may have resulted in longer wait times for an available bed, thereby minimizing the impact of the protocol on time from triage to administration of antibiotics. COVID-19 may also have contributed to postimplementation mortality. Of note, barcode medication administration (BCMA) was implemented in the ED in May 2019, which may account for undocumented delays in antibiotic administration as staff may have been unfamiliar with BCMA workflow.

Due to the retrospective nature of a chart review, the data rely on the timely input and accuracy of documented information. Data after the patient’s ED encounter (except inpatient hospitalization and deaths during the implementation period) were not collected due to the scope of the program being limited to the ED only. Last, this protocol was implemented at a single site, and the generalizability to implement the same protocol at other VA medical centers may be limited. After reaching out to other VA sites and several non-VA facilities, we were unable to find a site with a similar protocol or program emphasizing the importance of timely care, although there may have been established laboratory test and medication order sets within the EHR.

Future Direction

The newly established FN order sets will continue to streamline clinical decision making and antibiotic selection in this population. In our study, we learned that most patients coming through the ED were being treated with palliative intent. As a result, these patients also may have a higher risk for complications like FN. We hope to further analyze the impact on this group and consider the role of empiric dose reduction or increased G-CSF support to minimize FN.

More than half of the patients who were admitted to the inpatient service, remained in extended care for > 72 hours. Inpatient recovery time may cause delays in future cancer treatment cycles, dose reductions, and contribute to an overall decline in performance status. Six patients in the pre-implementation phase and 1 in the postimplementation phase were eligible for outpatient management per independent Multinational Association of Supportive Care in Cancer assessment. To increase comfort, a future goal would be to create an outpatient treatment order set on discharge from the ED to help identify and outline treatment options for low-risk patients. In addition to the ED, training staff in clinics with a similar protocol may enhance the identification of patients with FN. This may require a tailored protocol for this location using health technicians in taking vital signs before the HCP visit.

This protocol helped establish “code sepsis.” Code sepsis alerts are broadcast to alert pertinent members of the health care team to provide immediate medical attention to the veteran. Pharmacy can expedite the compounding of antibiotics and record review while radiology prioritizes the portable X-ray for quick and efficient imaging. The nursing team comes ready to administer antibiotics once cultures are drawn. The HCP's attention is focused on the physical examination to determine any additional steps/care that need to be accomplished. At our site, we plan to continue HCP, nursing, and other team member education on this oncologic emergency and the availability of a streamlined protocol. We would like to re-assess the data with a long team study now that the protocol has been in place for 3 years. We hope to continue to provide strong patient care with enhanced adherence to guidelines for patients with FN presenting to RLRVAMC.

Conclusions

Early identification and timely empiric antibiotic therapy are critical to improving outcomes for patients presenting to the ED with FN. The neutropenic fever protocol reduced time to antibiotics by about 1 hour with a higher percentage of patients receiving them in < 1 hour. Additional optimization of the order sets along with increased protocol comfort and staff education will help further reduce the time to antibiotic administration in alignment with guideline recommendations.

Febrile neutropenia (FN) is a life-threatening oncologic emergency requiring timely evaluation and treatment. Chemotherapy-induced neutropenia is a major risk for life-threatening infection, and fever may be the only sign.^1,2 Unrecognized fever can progress to sepsis and may result in increased morbidity and mortality. FN is defined as the presence of fever with a single temperature of  ≥ 38.3 °C or a sustained temperature > 38 °C sustained over 1 hour with an absolute neutrophil count (ANC) of < 500 cells/mm³ or < 1000 cells/mm³ and expected to decrease to < 500 within 48 hours.^2,3 It is critical to quickly identify these patients on presentation to the emergency department (ED) and take appropriate steps to initiate treatment as soon as possible. To streamline care, the American Society of Clinical Oncology (ASCO) recommends that laboratory assessments be initiated within 15 minutes of triage and empiric antibiotic therapy be administered within 1 hour.²

In alignment with the Infectious Disease Society of America (IDSA) guidelines, the National Comprehensive Cancer Network (NCCN) highlights the importance of the initial assessment of fever and neutropenia and presents available treatment options for both inpatient and outpatient management of FN.¹ Once patients are identified, the appropriate laboratory tests and physical assessments should be initiated immediately. These tests include a complete blood count with differential, complete metabolic panel (CMP), and blood cultures from 2 separate IV sites.^1-3 The guidelines offer additional suggestions for cultures and radiographic assessments that may be completed based on clinical presentation.

Several available studies provide insight into methods of protocol creation and possible barriers to timely management. Previous research showed that an FN protocol for pediatric oncology patients aimed at antibiotic administration within 1 hour showed significant improvement from 35.0% to 55.4% of patients being treated on time.^3,4 Prescribers became more comfortable in using the protocol, and timing improved as the study progressed. Barriers noted were inconsistent ED triage, rotating ED staff, and limited understanding of the protocol.³ Yoshida and colleagues worked with the same population. Over the course of 1 year, 60% of patients were receiving antibiotics within 1 hour. The mean time decreased from 83 to 65 minutes, which the study investigators noted would continue to decrease with increased protocol comfort and use.⁵ Mattison and colleagues used nursing staff to identify patients with FN and begin antibiotic treatment. On triage, nurses took note of a temperature of > 38 °C or a sepsislike clinical picture that initiated their antibiotic proforma.^4,6 This resulted in 48.1% of patients receiving antibiotics within 15 minutes and 63.3% overall within 30 minutes of arrival.⁵ Other barriers to consider are ED crowding and the admission of higher acuity patients, which may delay the treatment of patients with FN.

The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana is a level 1A facility serving about 62,000 veterans annually and more than 13,000 unique veterans visiting the ED. RLRVAMC ED staff rotate often so the creation of a process will facilitate appropriate treatment as quickly as possible. The purpose of this protocol was to improve the mean time from triage to administration of antibiotics for patients with FN presenting to the ED.

Implementation

To quantify the perceived delay in antibiotic prescribing, a pre- and postprotocol retrospective chart review of patients who presented with FN to the RLRVAMC ED was conducted. Patients were identified through the electronic health record (EHR) based on 3 criteria: recorded/reported fever as defined above, ANC < 1000 cells/mm³, and administration of cancer treatment (IV and oral) within 4 weeks. The data collected in the postimplementation phase were identical to the pre-implementation phase. This included timing of blood cultures, choice/appropriateness of antibiotics based on guidelines, and length of admission. The pre-implementation period started on August 1, 2018, and ended on August 1, 2019, to allow for an adequate pre-implementation sample size. The protocol was then implemented on October 1, 2019, and data collection for the postimplementation phase began on October 1,2019, and ended on October 1, 2020.

The protocol was accompanied by EHR order sets initiated by both nurses and health care practitioners (HCPs), including physicians, nurse practitioners, and physician assistants. The nursing order set consisted of vitals and appropriate laboratory monitoring, and the practitioner order set housed medication orders and additional clinical monitoring for more patient-specific scenarios. On identification of at-risk patients, the nursing staff could initiate the neutropenic fever protocol without consulting an HCP. The patient was then assigned a higher acuity rank, and the HCP was tasked with seeing the patient immediately. In conjunction with a complete physical assessment, the HCP ordered appropriate antibiotics through the designated order set to streamline antibiotic selection. Antibiotic options included cefepime or piperacillin-tazobactam, and vancomycin when clinically indicated. Alternatives for patients allergic to penicillin also were available. The protocol intended to streamline workup and antibiotic selection but was not designed as a substitute for solid clinical decision making and complete assessment on behalf of the HCP; therefore, additional workup may have been necessary and documented in the EHR.

Findings

This patient population comprised 17 patients pre-implementation and 12 patients postimplementation, most of whom had solid tumor malignancies (88.2% and 83.3%, respectively) receiving platinum, taxane, or antimetabolite-based chemotherapy. In the pre-implementation group, most patients (70.5%) coming through the ED were treated with palliative intent. Only 25% of these received any prophylactic granulocyte-colony stimulating factor (G-CSF) based on risk for FN. The mean time from triage to the first dose of antibiotics decreased from 3.3 hours before protocol implementation to 2.3 hours after. Only 6% in the pre-implementation group compared with 17% in the postimplementation group received the first dose of antibiotics within the recommended 1-hour interval from triage. The most common antibiotics administered were cefepime and vancomycin. Eleven patients in each group (65% and 92%, respectively) were admitted to the inpatient service for further care, with 10 and 8 patients, respectively, experiencing a hospitalization > 72 hours. Of note, 41% of patients died pre-implementation vs 17% postimplementation.

Interpretation

The goal of this protocol was to optimize ED care of patients presenting with FN to better align with guideline-recommended time lines and antibiotics. The mean time from triage to administration of antibiotics decreased by 1.0 hour from the pre- to postimplementation phase, similar to the study by Mattison and colleagues.³ When removing an outlier from the postimplementation group, the mean time from triage to first dose further decreased to 1.8 hours. The percentage of patients receiving antibiotics within 1 hour of triage nearly tripled from 6% to 17%. Additionally, the percentage of patients empirically treated with appropriate antibiotics consistent with NCCN/ASCO/IDSA guidelines increased from 65% to 83%. Although goals for the optimization of care have not yet been reached, this protocol is the first step in the right direction.

Limitations

Several limitations and concerns arise when implementing a new protocol or workflow process. Overall, these limitations may contribute to delays, such as the willingness of team members to use an unfamiliar protocol or issues locating a new protocol. The nursing staff is challenged to triage patients quickly, which may add to an already busy environment. Frequent physician turnover may require more frequent education sessions. Also, a lag time between implementation and using the protocol may result in decreased protocol use during the designated postimplementation data collection phase.

On review, ED staff were excited to find a protocol that streamlined decision making and increased awareness for patients at risk. The COVID-19 pandemic may have been a confounder for the postimplementation phase. Data may have been skewed as some patients might have elected to stay at home to avoid potential COVID-19 exposure in the ED. Additionally, increased ED use by patients with COVID-19 may have resulted in longer wait times for an available bed, thereby minimizing the impact of the protocol on time from triage to administration of antibiotics. COVID-19 may also have contributed to postimplementation mortality. Of note, barcode medication administration (BCMA) was implemented in the ED in May 2019, which may account for undocumented delays in antibiotic administration as staff may have been unfamiliar with BCMA workflow.

Due to the retrospective nature of a chart review, the data rely on the timely input and accuracy of documented information. Data after the patient’s ED encounter (except inpatient hospitalization and deaths during the implementation period) were not collected due to the scope of the program being limited to the ED only. Last, this protocol was implemented at a single site, and the generalizability to implement the same protocol at other VA medical centers may be limited. After reaching out to other VA sites and several non-VA facilities, we were unable to find a site with a similar protocol or program emphasizing the importance of timely care, although there may have been established laboratory test and medication order sets within the EHR.

Future Direction

The newly established FN order sets will continue to streamline clinical decision making and antibiotic selection in this population. In our study, we learned that most patients coming through the ED were being treated with palliative intent. As a result, these patients also may have a higher risk for complications like FN. We hope to further analyze the impact on this group and consider the role of empiric dose reduction or increased G-CSF support to minimize FN.

More than half of the patients who were admitted to the inpatient service, remained in extended care for > 72 hours. Inpatient recovery time may cause delays in future cancer treatment cycles, dose reductions, and contribute to an overall decline in performance status. Six patients in the pre-implementation phase and 1 in the postimplementation phase were eligible for outpatient management per independent Multinational Association of Supportive Care in Cancer assessment. To increase comfort, a future goal would be to create an outpatient treatment order set on discharge from the ED to help identify and outline treatment options for low-risk patients. In addition to the ED, training staff in clinics with a similar protocol may enhance the identification of patients with FN. This may require a tailored protocol for this location using health technicians in taking vital signs before the HCP visit.

This protocol helped establish “code sepsis.” Code sepsis alerts are broadcast to alert pertinent members of the health care team to provide immediate medical attention to the veteran. Pharmacy can expedite the compounding of antibiotics and record review while radiology prioritizes the portable X-ray for quick and efficient imaging. The nursing team comes ready to administer antibiotics once cultures are drawn. The HCP's attention is focused on the physical examination to determine any additional steps/care that need to be accomplished. At our site, we plan to continue HCP, nursing, and other team member education on this oncologic emergency and the availability of a streamlined protocol. We would like to re-assess the data with a long team study now that the protocol has been in place for 3 years. We hope to continue to provide strong patient care with enhanced adherence to guidelines for patients with FN presenting to RLRVAMC.

Conclusions

Early identification and timely empiric antibiotic therapy are critical to improving outcomes for patients presenting to the ED with FN. The neutropenic fever protocol reduced time to antibiotics by about 1 hour with a higher percentage of patients receiving them in < 1 hour. Additional optimization of the order sets along with increased protocol comfort and staff education will help further reduce the time to antibiotic administration in alignment with guideline recommendations.

Febrile neutropenia (FN) is a life-threatening oncologic emergency requiring timely evaluation and treatment. Chemotherapy-induced neutropenia is a major risk for life-threatening infection, and fever may be the only sign.^1,2 Unrecognized fever can progress to sepsis and may result in increased morbidity and mortality. FN is defined as the presence of fever with a single temperature of  ≥ 38.3 °C or a sustained temperature > 38 °C sustained over 1 hour with an absolute neutrophil count (ANC) of < 500 cells/mm³ or < 1000 cells/mm³ and expected to decrease to < 500 within 48 hours.^2,3 It is critical to quickly identify these patients on presentation to the emergency department (ED) and take appropriate steps to initiate treatment as soon as possible. To streamline care, the American Society of Clinical Oncology (ASCO) recommends that laboratory assessments be initiated within 15 minutes of triage and empiric antibiotic therapy be administered within 1 hour.²

In alignment with the Infectious Disease Society of America (IDSA) guidelines, the National Comprehensive Cancer Network (NCCN) highlights the importance of the initial assessment of fever and neutropenia and presents available treatment options for both inpatient and outpatient management of FN.¹ Once patients are identified, the appropriate laboratory tests and physical assessments should be initiated immediately. These tests include a complete blood count with differential, complete metabolic panel (CMP), and blood cultures from 2 separate IV sites.^1-3 The guidelines offer additional suggestions for cultures and radiographic assessments that may be completed based on clinical presentation.

Several available studies provide insight into methods of protocol creation and possible barriers to timely management. Previous research showed that an FN protocol for pediatric oncology patients aimed at antibiotic administration within 1 hour showed significant improvement from 35.0% to 55.4% of patients being treated on time.^3,4 Prescribers became more comfortable in using the protocol, and timing improved as the study progressed. Barriers noted were inconsistent ED triage, rotating ED staff, and limited understanding of the protocol.³ Yoshida and colleagues worked with the same population. Over the course of 1 year, 60% of patients were receiving antibiotics within 1 hour. The mean time decreased from 83 to 65 minutes, which the study investigators noted would continue to decrease with increased protocol comfort and use.⁵ Mattison and colleagues used nursing staff to identify patients with FN and begin antibiotic treatment. On triage, nurses took note of a temperature of > 38 °C or a sepsislike clinical picture that initiated their antibiotic proforma.^4,6 This resulted in 48.1% of patients receiving antibiotics within 15 minutes and 63.3% overall within 30 minutes of arrival.⁵ Other barriers to consider are ED crowding and the admission of higher acuity patients, which may delay the treatment of patients with FN.

The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana is a level 1A facility serving about 62,000 veterans annually and more than 13,000 unique veterans visiting the ED. RLRVAMC ED staff rotate often so the creation of a process will facilitate appropriate treatment as quickly as possible. The purpose of this protocol was to improve the mean time from triage to administration of antibiotics for patients with FN presenting to the ED.

Implementation

To quantify the perceived delay in antibiotic prescribing, a pre- and postprotocol retrospective chart review of patients who presented with FN to the RLRVAMC ED was conducted. Patients were identified through the electronic health record (EHR) based on 3 criteria: recorded/reported fever as defined above, ANC < 1000 cells/mm³, and administration of cancer treatment (IV and oral) within 4 weeks. The data collected in the postimplementation phase were identical to the pre-implementation phase. This included timing of blood cultures, choice/appropriateness of antibiotics based on guidelines, and length of admission. The pre-implementation period started on August 1, 2018, and ended on August 1, 2019, to allow for an adequate pre-implementation sample size. The protocol was then implemented on October 1, 2019, and data collection for the postimplementation phase began on October 1,2019, and ended on October 1, 2020.

The protocol was accompanied by EHR order sets initiated by both nurses and health care practitioners (HCPs), including physicians, nurse practitioners, and physician assistants. The nursing order set consisted of vitals and appropriate laboratory monitoring, and the practitioner order set housed medication orders and additional clinical monitoring for more patient-specific scenarios. On identification of at-risk patients, the nursing staff could initiate the neutropenic fever protocol without consulting an HCP. The patient was then assigned a higher acuity rank, and the HCP was tasked with seeing the patient immediately. In conjunction with a complete physical assessment, the HCP ordered appropriate antibiotics through the designated order set to streamline antibiotic selection. Antibiotic options included cefepime or piperacillin-tazobactam, and vancomycin when clinically indicated. Alternatives for patients allergic to penicillin also were available. The protocol intended to streamline workup and antibiotic selection but was not designed as a substitute for solid clinical decision making and complete assessment on behalf of the HCP; therefore, additional workup may have been necessary and documented in the EHR.

Findings

This patient population comprised 17 patients pre-implementation and 12 patients postimplementation, most of whom had solid tumor malignancies (88.2% and 83.3%, respectively) receiving platinum, taxane, or antimetabolite-based chemotherapy. In the pre-implementation group, most patients (70.5%) coming through the ED were treated with palliative intent. Only 25% of these received any prophylactic granulocyte-colony stimulating factor (G-CSF) based on risk for FN. The mean time from triage to the first dose of antibiotics decreased from 3.3 hours before protocol implementation to 2.3 hours after. Only 6% in the pre-implementation group compared with 17% in the postimplementation group received the first dose of antibiotics within the recommended 1-hour interval from triage. The most common antibiotics administered were cefepime and vancomycin. Eleven patients in each group (65% and 92%, respectively) were admitted to the inpatient service for further care, with 10 and 8 patients, respectively, experiencing a hospitalization > 72 hours. Of note, 41% of patients died pre-implementation vs 17% postimplementation.

Interpretation

The goal of this protocol was to optimize ED care of patients presenting with FN to better align with guideline-recommended time lines and antibiotics. The mean time from triage to administration of antibiotics decreased by 1.0 hour from the pre- to postimplementation phase, similar to the study by Mattison and colleagues.³ When removing an outlier from the postimplementation group, the mean time from triage to first dose further decreased to 1.8 hours. The percentage of patients receiving antibiotics within 1 hour of triage nearly tripled from 6% to 17%. Additionally, the percentage of patients empirically treated with appropriate antibiotics consistent with NCCN/ASCO/IDSA guidelines increased from 65% to 83%. Although goals for the optimization of care have not yet been reached, this protocol is the first step in the right direction.

Limitations

Several limitations and concerns arise when implementing a new protocol or workflow process. Overall, these limitations may contribute to delays, such as the willingness of team members to use an unfamiliar protocol or issues locating a new protocol. The nursing staff is challenged to triage patients quickly, which may add to an already busy environment. Frequent physician turnover may require more frequent education sessions. Also, a lag time between implementation and using the protocol may result in decreased protocol use during the designated postimplementation data collection phase.

On review, ED staff were excited to find a protocol that streamlined decision making and increased awareness for patients at risk. The COVID-19 pandemic may have been a confounder for the postimplementation phase. Data may have been skewed as some patients might have elected to stay at home to avoid potential COVID-19 exposure in the ED. Additionally, increased ED use by patients with COVID-19 may have resulted in longer wait times for an available bed, thereby minimizing the impact of the protocol on time from triage to administration of antibiotics. COVID-19 may also have contributed to postimplementation mortality. Of note, barcode medication administration (BCMA) was implemented in the ED in May 2019, which may account for undocumented delays in antibiotic administration as staff may have been unfamiliar with BCMA workflow.

Due to the retrospective nature of a chart review, the data rely on the timely input and accuracy of documented information. Data after the patient’s ED encounter (except inpatient hospitalization and deaths during the implementation period) were not collected due to the scope of the program being limited to the ED only. Last, this protocol was implemented at a single site, and the generalizability to implement the same protocol at other VA medical centers may be limited. After reaching out to other VA sites and several non-VA facilities, we were unable to find a site with a similar protocol or program emphasizing the importance of timely care, although there may have been established laboratory test and medication order sets within the EHR.

Future Direction

The newly established FN order sets will continue to streamline clinical decision making and antibiotic selection in this population. In our study, we learned that most patients coming through the ED were being treated with palliative intent. As a result, these patients also may have a higher risk for complications like FN. We hope to further analyze the impact on this group and consider the role of empiric dose reduction or increased G-CSF support to minimize FN.

More than half of the patients who were admitted to the inpatient service, remained in extended care for > 72 hours. Inpatient recovery time may cause delays in future cancer treatment cycles, dose reductions, and contribute to an overall decline in performance status. Six patients in the pre-implementation phase and 1 in the postimplementation phase were eligible for outpatient management per independent Multinational Association of Supportive Care in Cancer assessment. To increase comfort, a future goal would be to create an outpatient treatment order set on discharge from the ED to help identify and outline treatment options for low-risk patients. In addition to the ED, training staff in clinics with a similar protocol may enhance the identification of patients with FN. This may require a tailored protocol for this location using health technicians in taking vital signs before the HCP visit.

This protocol helped establish “code sepsis.” Code sepsis alerts are broadcast to alert pertinent members of the health care team to provide immediate medical attention to the veteran. Pharmacy can expedite the compounding of antibiotics and record review while radiology prioritizes the portable X-ray for quick and efficient imaging. The nursing team comes ready to administer antibiotics once cultures are drawn. The HCP's attention is focused on the physical examination to determine any additional steps/care that need to be accomplished. At our site, we plan to continue HCP, nursing, and other team member education on this oncologic emergency and the availability of a streamlined protocol. We would like to re-assess the data with a long team study now that the protocol has been in place for 3 years. We hope to continue to provide strong patient care with enhanced adherence to guidelines for patients with FN presenting to RLRVAMC.

Conclusions

Early identification and timely empiric antibiotic therapy are critical to improving outcomes for patients presenting to the ED with FN. The neutropenic fever protocol reduced time to antibiotics by about 1 hour with a higher percentage of patients receiving them in < 1 hour. Additional optimization of the order sets along with increased protocol comfort and staff education will help further reduce the time to antibiotic administration in alignment with guideline recommendations.

The latest research on disease-modifying therapies presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2023 annual meeting is reported by Dr Jennifer Graves from the University of California, San Diego. 

Dr Graves first discusses a small study exploring the effects of an intermittent calorie restriction (ICR) diet on adipokine levels, metabolic and immune/inflammatory biomarkers, and MRI measurements. Researchers found that short-term ICR can improve metabolic and immunologic profiles in patients with MS.  

Next, Dr Graves discusses a trial that successively measured changes in proteins in the cerebrospinal fluid of patients treated with tolebrutinib and ocrelizumab as evidence of therapeutic efficacy. This study provides early evidence of the impact of these medications directly in the central nervous system. 

She then details a study evaluating autologous hematopoietic stem cell transplant (aHSCT) as an MS treatment. The study found that aHSCT has a durable effect for up to 5-10 years compared to our current available regimens.  

Finally, Dr Graves highlights the National MS Society Barancik Prize winner Dr Ruth Ann Marrie. Dr Marrie is a pioneer for her research in comorbidities and their effect on MS treatment decisions, especially in choosing disease-modifying therapies.  

--

Jennifer S.O. Graves, MD, PhD, Associate Professor, Director Neuroimmunology Research, Department of Neurosciences, University of California, San Diego  

Jennifer S.O. Graves, MD, PhD, has disclosed the following relevant financial relationships: 

Serve(d) on an advisory board for: TG Therapeutics; Bayer 

Received research grant from: Sanofi; EMD Serono; Biogen; ATARA; Octave 

The latest research on disease-modifying therapies presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2023 annual meeting is reported by Dr Jennifer Graves from the University of California, San Diego. 

Dr Graves first discusses a small study exploring the effects of an intermittent calorie restriction (ICR) diet on adipokine levels, metabolic and immune/inflammatory biomarkers, and MRI measurements. Researchers found that short-term ICR can improve metabolic and immunologic profiles in patients with MS.  

Next, Dr Graves discusses a trial that successively measured changes in proteins in the cerebrospinal fluid of patients treated with tolebrutinib and ocrelizumab as evidence of therapeutic efficacy. This study provides early evidence of the impact of these medications directly in the central nervous system. 

She then details a study evaluating autologous hematopoietic stem cell transplant (aHSCT) as an MS treatment. The study found that aHSCT has a durable effect for up to 5-10 years compared to our current available regimens.  

Finally, Dr Graves highlights the National MS Society Barancik Prize winner Dr Ruth Ann Marrie. Dr Marrie is a pioneer for her research in comorbidities and their effect on MS treatment decisions, especially in choosing disease-modifying therapies.  

--

Jennifer S.O. Graves, MD, PhD, Associate Professor, Director Neuroimmunology Research, Department of Neurosciences, University of California, San Diego  

Jennifer S.O. Graves, MD, PhD, has disclosed the following relevant financial relationships: 

Serve(d) on an advisory board for: TG Therapeutics; Bayer 

Received research grant from: Sanofi; EMD Serono; Biogen; ATARA; Octave 

The latest research on disease-modifying therapies presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2023 annual meeting is reported by Dr Jennifer Graves from the University of California, San Diego. 

Dr Graves first discusses a small study exploring the effects of an intermittent calorie restriction (ICR) diet on adipokine levels, metabolic and immune/inflammatory biomarkers, and MRI measurements. Researchers found that short-term ICR can improve metabolic and immunologic profiles in patients with MS.  

Next, Dr Graves discusses a trial that successively measured changes in proteins in the cerebrospinal fluid of patients treated with tolebrutinib and ocrelizumab as evidence of therapeutic efficacy. This study provides early evidence of the impact of these medications directly in the central nervous system. 

She then details a study evaluating autologous hematopoietic stem cell transplant (aHSCT) as an MS treatment. The study found that aHSCT has a durable effect for up to 5-10 years compared to our current available regimens.  

Finally, Dr Graves highlights the National MS Society Barancik Prize winner Dr Ruth Ann Marrie. Dr Marrie is a pioneer for her research in comorbidities and their effect on MS treatment decisions, especially in choosing disease-modifying therapies.  

--

Jennifer S.O. Graves, MD, PhD, Associate Professor, Director Neuroimmunology Research, Department of Neurosciences, University of California, San Diego  

Jennifer S.O. Graves, MD, PhD, has disclosed the following relevant financial relationships: 

Serve(d) on an advisory board for: TG Therapeutics; Bayer 

Received research grant from: Sanofi; EMD Serono; Biogen; ATARA; Octave 

The history and findings in this case are suggestive of small cell carcinoma of the prostate (SCCP). 

SCCP is a rare and aggressive cancer that comprises 1%–5% of all prostate cancers (if mixed cases with adenocarcinoma are included). Similar to small cell carcinoma of the lung or other small cell primaries, SCCP is characterized by a primary tumor of the prostate gland that expresses small cell morphology and high-grade features, including minimal cytoplasm, nuclear molding, fine chromatin pattern, extensive tumor necrosis and apoptosis, variable tumor giant cells, and a high mitotic rate. Patients often have disproportionally low PSA levels despite having large metastatic burden and visceral disease. Pathologic diagnosis is made on the basis of prostate biopsy using characteristics of small cell tumors and immunohistochemical staining for neuroendocrine markers, such as CD56, chromogranin A, synaptophysin, and neuron-specific enolase.

SCCP arises de novo in approximately 50% of cases; it also occurs in patients with previous or concomitant prostate adenocarcinoma. Patients are often symptomatic at diagnosis because of the extent of the tumor. The aggressive nature and high proliferation rate associated with SCCP result in an increased risk for lytic or blastic bone, visceral, and brain metastases. In addition, paraneoplastic syndromes (eg, the syndrome of inappropriate antidiuretic hormone secretion, Cushing syndrome, and hypercalcemia) frequently occur as a result of the release of peptides.

SCCP metastasizes early in its course and is associated with a poor prognosis. It has a median survival of < 1 year. Fluorodeoxyglucose PET-CT are useful for staging and monitoring treatment response; in addition, given the disease's predilection for brain metastases, MRI of the brain should be considered. 

The optimal treatment for patients with metastatic SCCP has not yet been determined. Localized SCCP is treated aggressively, typically with a multimodality approach involving chemotherapy with concurrent or consolidative radiotherapy.

According to 2023 guidelines from the National Comprehensive Cancer Network (NCCN), platinum-based combination chemotherapy (cisplatin-etoposide, carboplatin-etoposide, docetaxel-carboplatin, cabazitaxel-carboplatin) is the first-line approach for patients with metastatic disease.

Physicians are also advised to consult the NCCN guidelines for small cell lung cancer because the behavior of SCCP is similar to that of small cell carcinoma of the lung. Immunotherapy with pembrolizumab may be used for platinum-resistant extrapulmonary small cell carcinoma. However, sipuleucel-T is not recommended for patients with SCCP. 
 

Chad R. Tracy, MD, Professor; Director, Minimally Invasive Surgery, Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, Iowa

Chad R. Tracy, MD, has disclosed the following relevant financial relationships:

Serve(d) as a consultant for: CVICO Medical Solutions.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of small cell carcinoma of the prostate (SCCP). 

SCCP is a rare and aggressive cancer that comprises 1%–5% of all prostate cancers (if mixed cases with adenocarcinoma are included). Similar to small cell carcinoma of the lung or other small cell primaries, SCCP is characterized by a primary tumor of the prostate gland that expresses small cell morphology and high-grade features, including minimal cytoplasm, nuclear molding, fine chromatin pattern, extensive tumor necrosis and apoptosis, variable tumor giant cells, and a high mitotic rate. Patients often have disproportionally low PSA levels despite having large metastatic burden and visceral disease. Pathologic diagnosis is made on the basis of prostate biopsy using characteristics of small cell tumors and immunohistochemical staining for neuroendocrine markers, such as CD56, chromogranin A, synaptophysin, and neuron-specific enolase.

SCCP arises de novo in approximately 50% of cases; it also occurs in patients with previous or concomitant prostate adenocarcinoma. Patients are often symptomatic at diagnosis because of the extent of the tumor. The aggressive nature and high proliferation rate associated with SCCP result in an increased risk for lytic or blastic bone, visceral, and brain metastases. In addition, paraneoplastic syndromes (eg, the syndrome of inappropriate antidiuretic hormone secretion, Cushing syndrome, and hypercalcemia) frequently occur as a result of the release of peptides.

SCCP metastasizes early in its course and is associated with a poor prognosis. It has a median survival of < 1 year. Fluorodeoxyglucose PET-CT are useful for staging and monitoring treatment response; in addition, given the disease's predilection for brain metastases, MRI of the brain should be considered. 

The optimal treatment for patients with metastatic SCCP has not yet been determined. Localized SCCP is treated aggressively, typically with a multimodality approach involving chemotherapy with concurrent or consolidative radiotherapy.

According to 2023 guidelines from the National Comprehensive Cancer Network (NCCN), platinum-based combination chemotherapy (cisplatin-etoposide, carboplatin-etoposide, docetaxel-carboplatin, cabazitaxel-carboplatin) is the first-line approach for patients with metastatic disease.

Physicians are also advised to consult the NCCN guidelines for small cell lung cancer because the behavior of SCCP is similar to that of small cell carcinoma of the lung. Immunotherapy with pembrolizumab may be used for platinum-resistant extrapulmonary small cell carcinoma. However, sipuleucel-T is not recommended for patients with SCCP. 
 

Chad R. Tracy, MD, Professor; Director, Minimally Invasive Surgery, Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, Iowa

Chad R. Tracy, MD, has disclosed the following relevant financial relationships:

Serve(d) as a consultant for: CVICO Medical Solutions.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of small cell carcinoma of the prostate (SCCP). 

SCCP is a rare and aggressive cancer that comprises 1%–5% of all prostate cancers (if mixed cases with adenocarcinoma are included). Similar to small cell carcinoma of the lung or other small cell primaries, SCCP is characterized by a primary tumor of the prostate gland that expresses small cell morphology and high-grade features, including minimal cytoplasm, nuclear molding, fine chromatin pattern, extensive tumor necrosis and apoptosis, variable tumor giant cells, and a high mitotic rate. Patients often have disproportionally low PSA levels despite having large metastatic burden and visceral disease. Pathologic diagnosis is made on the basis of prostate biopsy using characteristics of small cell tumors and immunohistochemical staining for neuroendocrine markers, such as CD56, chromogranin A, synaptophysin, and neuron-specific enolase.

SCCP arises de novo in approximately 50% of cases; it also occurs in patients with previous or concomitant prostate adenocarcinoma. Patients are often symptomatic at diagnosis because of the extent of the tumor. The aggressive nature and high proliferation rate associated with SCCP result in an increased risk for lytic or blastic bone, visceral, and brain metastases. In addition, paraneoplastic syndromes (eg, the syndrome of inappropriate antidiuretic hormone secretion, Cushing syndrome, and hypercalcemia) frequently occur as a result of the release of peptides.

SCCP metastasizes early in its course and is associated with a poor prognosis. It has a median survival of < 1 year. Fluorodeoxyglucose PET-CT are useful for staging and monitoring treatment response; in addition, given the disease's predilection for brain metastases, MRI of the brain should be considered. 

The optimal treatment for patients with metastatic SCCP has not yet been determined. Localized SCCP is treated aggressively, typically with a multimodality approach involving chemotherapy with concurrent or consolidative radiotherapy.

According to 2023 guidelines from the National Comprehensive Cancer Network (NCCN), platinum-based combination chemotherapy (cisplatin-etoposide, carboplatin-etoposide, docetaxel-carboplatin, cabazitaxel-carboplatin) is the first-line approach for patients with metastatic disease.

Physicians are also advised to consult the NCCN guidelines for small cell lung cancer because the behavior of SCCP is similar to that of small cell carcinoma of the lung. Immunotherapy with pembrolizumab may be used for platinum-resistant extrapulmonary small cell carcinoma. However, sipuleucel-T is not recommended for patients with SCCP. 
 

Chad R. Tracy, MD, Professor; Director, Minimally Invasive Surgery, Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, Iowa

Chad R. Tracy, MD, has disclosed the following relevant financial relationships:

Serve(d) as a consultant for: CVICO Medical Solutions.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Dermoscopy revealed an 8-mm scaly brown-black papule that lacked melanocytic features (pigment network, globules, streaks, or homogeneous blue or brown color) but had milia-like cysts and so-called “fat fingers” (short, straight to curved radial projections¹). These findings were consistent with a diagnosis of seborrheic keratosis (SK).

SKs go by many names and are often confused with nevi. Some patients might know them by such names as “age spots” or “liver spots.” Patients often have many SKs on their body; the back and skin folds are common locations. Patients may be unhappy about the way they look and may describe occasional discomfort when the SKs rub against clothes and inflammation that occurs spontaneously or with trauma.

Classic SKs have a well-demarcated border and waxy, stuck-on appearance. There are times when it is difficult to distinguish between an SK and a melanocytic lesion. Thus, a biopsy may be necessary. In addition, SKs are so common that collision lesions may occur. (Collision lesions result when 2 histologically distinct neoplasms occur adjacent to each other and cause an unusual clinical appearance with features of each lesion.) The atypical clinical features in a collision lesion may prompt a biopsy to exclude malignancy.

Dermoscopic features of SKs include well-demarcated borders, milia-like cysts (white circular inclusions), comedo-like openings (brown/black circular inclusions), fissures and ridges, hairpin vessels, and fat fingers.

Cryotherapy is a quick and efficient treatment when a patient would like the lesions removed. Curettage or light electrodessication may be less likely to cause post-inflammatory hypopigmentation in patients with darker skin types. These various destructive therapies are often considered cosmetic and are unlikely to be covered by insurance unless there is documentation of significant inflammation or discomfort. In this case, the lesion was not treated.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

Dermoscopy revealed an 8-mm scaly brown-black papule that lacked melanocytic features (pigment network, globules, streaks, or homogeneous blue or brown color) but had milia-like cysts and so-called “fat fingers” (short, straight to curved radial projections¹). These findings were consistent with a diagnosis of seborrheic keratosis (SK).

SKs go by many names and are often confused with nevi. Some patients might know them by such names as “age spots” or “liver spots.” Patients often have many SKs on their body; the back and skin folds are common locations. Patients may be unhappy about the way they look and may describe occasional discomfort when the SKs rub against clothes and inflammation that occurs spontaneously or with trauma.

Classic SKs have a well-demarcated border and waxy, stuck-on appearance. There are times when it is difficult to distinguish between an SK and a melanocytic lesion. Thus, a biopsy may be necessary. In addition, SKs are so common that collision lesions may occur. (Collision lesions result when 2 histologically distinct neoplasms occur adjacent to each other and cause an unusual clinical appearance with features of each lesion.) The atypical clinical features in a collision lesion may prompt a biopsy to exclude malignancy.

Dermoscopic features of SKs include well-demarcated borders, milia-like cysts (white circular inclusions), comedo-like openings (brown/black circular inclusions), fissures and ridges, hairpin vessels, and fat fingers.

Cryotherapy is a quick and efficient treatment when a patient would like the lesions removed. Curettage or light electrodessication may be less likely to cause post-inflammatory hypopigmentation in patients with darker skin types. These various destructive therapies are often considered cosmetic and are unlikely to be covered by insurance unless there is documentation of significant inflammation or discomfort. In this case, the lesion was not treated.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

Dermoscopy revealed an 8-mm scaly brown-black papule that lacked melanocytic features (pigment network, globules, streaks, or homogeneous blue or brown color) but had milia-like cysts and so-called “fat fingers” (short, straight to curved radial projections¹). These findings were consistent with a diagnosis of seborrheic keratosis (SK).

SKs go by many names and are often confused with nevi. Some patients might know them by such names as “age spots” or “liver spots.” Patients often have many SKs on their body; the back and skin folds are common locations. Patients may be unhappy about the way they look and may describe occasional discomfort when the SKs rub against clothes and inflammation that occurs spontaneously or with trauma.

Classic SKs have a well-demarcated border and waxy, stuck-on appearance. There are times when it is difficult to distinguish between an SK and a melanocytic lesion. Thus, a biopsy may be necessary. In addition, SKs are so common that collision lesions may occur. (Collision lesions result when 2 histologically distinct neoplasms occur adjacent to each other and cause an unusual clinical appearance with features of each lesion.) The atypical clinical features in a collision lesion may prompt a biopsy to exclude malignancy.

Dermoscopic features of SKs include well-demarcated borders, milia-like cysts (white circular inclusions), comedo-like openings (brown/black circular inclusions), fissures and ridges, hairpin vessels, and fat fingers.

Cryotherapy is a quick and efficient treatment when a patient would like the lesions removed. Curettage or light electrodessication may be less likely to cause post-inflammatory hypopigmentation in patients with darker skin types. These various destructive therapies are often considered cosmetic and are unlikely to be covered by insurance unless there is documentation of significant inflammation or discomfort. In this case, the lesion was not treated.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The Diagnosis: Darier Disease

A clinical diagnosis of Darier disease was made from the skin findings of pruritic, malodorous, keratotic papules in a seborrheic distribution and pathognomonic nail dystrophy, along with a family history that demonstrated autosomal-dominant inheritance. The ulcerations were suspected to be caused by a superimposed herpes simplex virus (HSV) infection in the form of eczema herpeticum. The clinical diagnosis was later confirmed via punch biopsy. Pathology results demonstrated focal acantholytic dyskeratosis, which was consistent with Darier disease given the focal nature and lack of acanthosis. The patient’s father and sister also were confirmed to have Darier disease by an outside dermatologist.

Darier disease is a rare keratinizing autosomaldominant genodermatosis that occurs due to a mutation in the ATP2A2 gene, which encodes a sarco/endoplasmic reticulum calcium ATPase pump that decreases cell adhesion between keratinocytes, leading to epidermal acantholysis and dyskeratosis and ultimately a disrupted skin barrier.^1,2 Darier disease often presents in childhood and adolescence with papules in a seborrheic distribution on the central chest and back (Figure, A); the intertriginous folds also may be involved. Darier disease can manifest with palmoplantar pits (Figure, B), a cobblestonelike texture of the oral mucosa, acrokeratosis verruciformis of Hopf, and nail findings with alternating red and white longitudinal streaks in the nail bed resembling a candy cane along with characteristic V nicking deformities of the nails themselves (Figure, C). Chronic flares may occur throughout one’s lifetime, with patients experiencing more symptoms in the summer months due to heat, sweat, and UV light exposure, as well as infections that irritate the skin and worsen dyskeratosis. Studies have revealed an association between Darier disease and neuropsychiatric conditions, including major depressive disorder, schizophrenia, and bipolar disorder.^3,4

The skin barrier is compromised in patients with Darier disease, thereby making secondary infection more likely to occur. Polymerase chain reaction swabs of our patient’s purulent ulcerations were positive for HSV type 1, further strengthening a diagnosis of secondary eczema herpeticum, which occurs when patients have widespread HSV superinfecting pre-existing skin conditions such as atopic dermatitis, Darier disease, and Hailey-Hailey disease.^5-7 The lesions are characterized by a monomorphic eruption of umbilicated vesicles on an erythematous base. Lesions can progress to punched-out ulcers and erosions with hemorrhagic crusts that coalesce, forming scalloped borders, similar to our patient’s presentation.⁸

Hailey-Hailey disease, a genodermatosis that alters calcium signaling with an autosomal-dominant inheritance pattern, was unlikely in our patient due to the presence of nail abnormalities and palmar pits that are characteristic of Darier disease. From a purely histopathologic standpoint, Grover disease was considered with skin biopsy demonstrating acantholytic dyskeratosis but was not compatible with the clinical context. Furthermore, trials of antibiotics with group A Streptococcus and Staphylococcus aureus coverage failed in our patient, and she lacked systemic symptoms that would be supportive of a cellulitis diagnosis. The punched-out lesions suggested that an isolated exacerbation of atopic dermatitis was not sufficient to explain all of the clinical findings.

Eczema herpeticum must be considered in the differential diagnosis for patients with underlying Darier disease and widespread ulcerations. Our patient had more recent punched-out ulcerations in the intertriginous regions, with other areas showing later stages of confluent ulcers with scalloped borders. Delayed diagnosis and treatment of eczema herpeticum combined with severe Darier disease can lead to increased risk for hospitalization and rarely fatality.^8,9

Our patient was started on intravenous acyclovir until the lesions crusted and then was transitioned to a suppressive dose of oral valacyclovir given the widespread distribution. The Darier disease itself was managed with topical steroids and a zinc oxide barrier, serving as protectants to pathogens through microscopic breaks in the skin. Our patient also had a mild case of candidal intertrigo that was exacerbated by obesity and managed with topical ketoconazole. Gabapentin, hydromorphone, and acetaminophen were used for pain. She was discharged 10 days after admission with substantial improvement of both the HSV lesions and the irritation from her Darier disease. At follow-up visits 20 days later and again 6 months after discharge, she had been feeling well without any HSV flares.

The eczema herpeticum likely arose from our patient’s chronic skin barrier impairment attributed to Darier disease, leading to the cutaneous inoculation of HSV. Our patient and her family members had never been evaluated by a dermatologist until late in life during this hospitalization. Medication compliance with a suppressive dose of oral valacyclovir and topical steroids is vital to prevent flares of both eczema herpeticum and Darier disease, respectively. This case highlights the importance of dermatology consultation for complex cutaneous findings, as delayed diagnosis and treatment can lead to increased morbidity and mortality.

The Diagnosis: Darier Disease

A clinical diagnosis of Darier disease was made from the skin findings of pruritic, malodorous, keratotic papules in a seborrheic distribution and pathognomonic nail dystrophy, along with a family history that demonstrated autosomal-dominant inheritance. The ulcerations were suspected to be caused by a superimposed herpes simplex virus (HSV) infection in the form of eczema herpeticum. The clinical diagnosis was later confirmed via punch biopsy. Pathology results demonstrated focal acantholytic dyskeratosis, which was consistent with Darier disease given the focal nature and lack of acanthosis. The patient’s father and sister also were confirmed to have Darier disease by an outside dermatologist.

Darier disease is a rare keratinizing autosomaldominant genodermatosis that occurs due to a mutation in the ATP2A2 gene, which encodes a sarco/endoplasmic reticulum calcium ATPase pump that decreases cell adhesion between keratinocytes, leading to epidermal acantholysis and dyskeratosis and ultimately a disrupted skin barrier.^1,2 Darier disease often presents in childhood and adolescence with papules in a seborrheic distribution on the central chest and back (Figure, A); the intertriginous folds also may be involved. Darier disease can manifest with palmoplantar pits (Figure, B), a cobblestonelike texture of the oral mucosa, acrokeratosis verruciformis of Hopf, and nail findings with alternating red and white longitudinal streaks in the nail bed resembling a candy cane along with characteristic V nicking deformities of the nails themselves (Figure, C). Chronic flares may occur throughout one’s lifetime, with patients experiencing more symptoms in the summer months due to heat, sweat, and UV light exposure, as well as infections that irritate the skin and worsen dyskeratosis. Studies have revealed an association between Darier disease and neuropsychiatric conditions, including major depressive disorder, schizophrenia, and bipolar disorder.^3,4

The skin barrier is compromised in patients with Darier disease, thereby making secondary infection more likely to occur. Polymerase chain reaction swabs of our patient’s purulent ulcerations were positive for HSV type 1, further strengthening a diagnosis of secondary eczema herpeticum, which occurs when patients have widespread HSV superinfecting pre-existing skin conditions such as atopic dermatitis, Darier disease, and Hailey-Hailey disease.^5-7 The lesions are characterized by a monomorphic eruption of umbilicated vesicles on an erythematous base. Lesions can progress to punched-out ulcers and erosions with hemorrhagic crusts that coalesce, forming scalloped borders, similar to our patient’s presentation.⁸

Hailey-Hailey disease, a genodermatosis that alters calcium signaling with an autosomal-dominant inheritance pattern, was unlikely in our patient due to the presence of nail abnormalities and palmar pits that are characteristic of Darier disease. From a purely histopathologic standpoint, Grover disease was considered with skin biopsy demonstrating acantholytic dyskeratosis but was not compatible with the clinical context. Furthermore, trials of antibiotics with group A Streptococcus and Staphylococcus aureus coverage failed in our patient, and she lacked systemic symptoms that would be supportive of a cellulitis diagnosis. The punched-out lesions suggested that an isolated exacerbation of atopic dermatitis was not sufficient to explain all of the clinical findings.

Eczema herpeticum must be considered in the differential diagnosis for patients with underlying Darier disease and widespread ulcerations. Our patient had more recent punched-out ulcerations in the intertriginous regions, with other areas showing later stages of confluent ulcers with scalloped borders. Delayed diagnosis and treatment of eczema herpeticum combined with severe Darier disease can lead to increased risk for hospitalization and rarely fatality.^8,9

Our patient was started on intravenous acyclovir until the lesions crusted and then was transitioned to a suppressive dose of oral valacyclovir given the widespread distribution. The Darier disease itself was managed with topical steroids and a zinc oxide barrier, serving as protectants to pathogens through microscopic breaks in the skin. Our patient also had a mild case of candidal intertrigo that was exacerbated by obesity and managed with topical ketoconazole. Gabapentin, hydromorphone, and acetaminophen were used for pain. She was discharged 10 days after admission with substantial improvement of both the HSV lesions and the irritation from her Darier disease. At follow-up visits 20 days later and again 6 months after discharge, she had been feeling well without any HSV flares.

The eczema herpeticum likely arose from our patient’s chronic skin barrier impairment attributed to Darier disease, leading to the cutaneous inoculation of HSV. Our patient and her family members had never been evaluated by a dermatologist until late in life during this hospitalization. Medication compliance with a suppressive dose of oral valacyclovir and topical steroids is vital to prevent flares of both eczema herpeticum and Darier disease, respectively. This case highlights the importance of dermatology consultation for complex cutaneous findings, as delayed diagnosis and treatment can lead to increased morbidity and mortality.

The Diagnosis: Darier Disease

A clinical diagnosis of Darier disease was made from the skin findings of pruritic, malodorous, keratotic papules in a seborrheic distribution and pathognomonic nail dystrophy, along with a family history that demonstrated autosomal-dominant inheritance. The ulcerations were suspected to be caused by a superimposed herpes simplex virus (HSV) infection in the form of eczema herpeticum. The clinical diagnosis was later confirmed via punch biopsy. Pathology results demonstrated focal acantholytic dyskeratosis, which was consistent with Darier disease given the focal nature and lack of acanthosis. The patient’s father and sister also were confirmed to have Darier disease by an outside dermatologist.

Darier disease is a rare keratinizing autosomaldominant genodermatosis that occurs due to a mutation in the ATP2A2 gene, which encodes a sarco/endoplasmic reticulum calcium ATPase pump that decreases cell adhesion between keratinocytes, leading to epidermal acantholysis and dyskeratosis and ultimately a disrupted skin barrier.^1,2 Darier disease often presents in childhood and adolescence with papules in a seborrheic distribution on the central chest and back (Figure, A); the intertriginous folds also may be involved. Darier disease can manifest with palmoplantar pits (Figure, B), a cobblestonelike texture of the oral mucosa, acrokeratosis verruciformis of Hopf, and nail findings with alternating red and white longitudinal streaks in the nail bed resembling a candy cane along with characteristic V nicking deformities of the nails themselves (Figure, C). Chronic flares may occur throughout one’s lifetime, with patients experiencing more symptoms in the summer months due to heat, sweat, and UV light exposure, as well as infections that irritate the skin and worsen dyskeratosis. Studies have revealed an association between Darier disease and neuropsychiatric conditions, including major depressive disorder, schizophrenia, and bipolar disorder.^3,4

The skin barrier is compromised in patients with Darier disease, thereby making secondary infection more likely to occur. Polymerase chain reaction swabs of our patient’s purulent ulcerations were positive for HSV type 1, further strengthening a diagnosis of secondary eczema herpeticum, which occurs when patients have widespread HSV superinfecting pre-existing skin conditions such as atopic dermatitis, Darier disease, and Hailey-Hailey disease.^5-7 The lesions are characterized by a monomorphic eruption of umbilicated vesicles on an erythematous base. Lesions can progress to punched-out ulcers and erosions with hemorrhagic crusts that coalesce, forming scalloped borders, similar to our patient’s presentation.⁸

Hailey-Hailey disease, a genodermatosis that alters calcium signaling with an autosomal-dominant inheritance pattern, was unlikely in our patient due to the presence of nail abnormalities and palmar pits that are characteristic of Darier disease. From a purely histopathologic standpoint, Grover disease was considered with skin biopsy demonstrating acantholytic dyskeratosis but was not compatible with the clinical context. Furthermore, trials of antibiotics with group A Streptococcus and Staphylococcus aureus coverage failed in our patient, and she lacked systemic symptoms that would be supportive of a cellulitis diagnosis. The punched-out lesions suggested that an isolated exacerbation of atopic dermatitis was not sufficient to explain all of the clinical findings.

Eczema herpeticum must be considered in the differential diagnosis for patients with underlying Darier disease and widespread ulcerations. Our patient had more recent punched-out ulcerations in the intertriginous regions, with other areas showing later stages of confluent ulcers with scalloped borders. Delayed diagnosis and treatment of eczema herpeticum combined with severe Darier disease can lead to increased risk for hospitalization and rarely fatality.^8,9

Our patient was started on intravenous acyclovir until the lesions crusted and then was transitioned to a suppressive dose of oral valacyclovir given the widespread distribution. The Darier disease itself was managed with topical steroids and a zinc oxide barrier, serving as protectants to pathogens through microscopic breaks in the skin. Our patient also had a mild case of candidal intertrigo that was exacerbated by obesity and managed with topical ketoconazole. Gabapentin, hydromorphone, and acetaminophen were used for pain. She was discharged 10 days after admission with substantial improvement of both the HSV lesions and the irritation from her Darier disease. At follow-up visits 20 days later and again 6 months after discharge, she had been feeling well without any HSV flares.

The eczema herpeticum likely arose from our patient’s chronic skin barrier impairment attributed to Darier disease, leading to the cutaneous inoculation of HSV. Our patient and her family members had never been evaluated by a dermatologist until late in life during this hospitalization. Medication compliance with a suppressive dose of oral valacyclovir and topical steroids is vital to prevent flares of both eczema herpeticum and Darier disease, respectively. This case highlights the importance of dermatology consultation for complex cutaneous findings, as delayed diagnosis and treatment can lead to increased morbidity and mortality.

The history and findings in this case are suggestive of Alzheimer's disease (AD), which probably was preceded by chronic traumatic encephalopathy (CTE).

AD is the most prevalent cause of cognitive impairment and dementia worldwide. Presently, approximately 50 million individuals are affected by AD; by 2050, the number of affected individuals globally is expected to reach 152 million. AD has a prolonged and progressive disease course that begins with neuropathologic changes in the brain years before onset of clinical manifestations. These changes include the accumulation of beta-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Neuroimaging studies have shown that beta-amyloid plaques begin to deposit in the brain ≥ 10 years before the start of cognitive decline. Patients with AD normally present with slowly progressive memory loss; as the disease progresses, other areas of cognition are affected. Patients may experience language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. Slowly progressive behavioral changes may also occur.

CTE is a neurodegenerative disorder that is believed to be the long-term consequence of repetitive head trauma. Its incidence is highest among athletes of high-impact sports, such as boxing or American football, and victims of domestic violence. Clinically, CTE can be indistinguishable from AD. Although neuropathologic differences exist, they can be confirmed only on postmortem examination. Patients with CTE may present with behavioral symptoms, such as aggression, depression, emotional lability, apathy, and suicidal feelings, as well as motor symptoms, including tremor, ataxia, incoordination, and dysarthria. Cognitive symptoms, including attention and concentration deficits and memory impairment, also occur. CTE is also associated with the development of dementia and may predispose patients to early-onset AD. 

Curative therapies do not exist for AD; thus, management centers on symptomatic treatment for neuropsychiatric or cognitive symptoms. Cholinesterase inhibitors and a partial N-methyl-D-aspartate antagonist are the standard medical therapies used in patients with AD. For patients with mild cognitive impairment or mild dementia, several newly approved antiamyloid therapies are also available. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021, and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Presently, both aducanumab and lecanemab are recommended only for the treatment of patients with mild cognitive impairment or mild dementia, the population in which their safety and efficacy were demonstrated in clinical trials. 

Psychotropic agents may be used to treat symptoms, such as depression, agitation, aggression, hallucinations, delusions, and sleep disorders, which can be problematic. Behavioral interventions may also be used, normally in combination with pharmacologic interventions (eg, anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations). Regular physical activity and exercise may help to delay disease progression and are recommended as an adjunct to the medical management of AD.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of Alzheimer's disease (AD), which probably was preceded by chronic traumatic encephalopathy (CTE).

AD is the most prevalent cause of cognitive impairment and dementia worldwide. Presently, approximately 50 million individuals are affected by AD; by 2050, the number of affected individuals globally is expected to reach 152 million. AD has a prolonged and progressive disease course that begins with neuropathologic changes in the brain years before onset of clinical manifestations. These changes include the accumulation of beta-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Neuroimaging studies have shown that beta-amyloid plaques begin to deposit in the brain ≥ 10 years before the start of cognitive decline. Patients with AD normally present with slowly progressive memory loss; as the disease progresses, other areas of cognition are affected. Patients may experience language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. Slowly progressive behavioral changes may also occur.

CTE is a neurodegenerative disorder that is believed to be the long-term consequence of repetitive head trauma. Its incidence is highest among athletes of high-impact sports, such as boxing or American football, and victims of domestic violence. Clinically, CTE can be indistinguishable from AD. Although neuropathologic differences exist, they can be confirmed only on postmortem examination. Patients with CTE may present with behavioral symptoms, such as aggression, depression, emotional lability, apathy, and suicidal feelings, as well as motor symptoms, including tremor, ataxia, incoordination, and dysarthria. Cognitive symptoms, including attention and concentration deficits and memory impairment, also occur. CTE is also associated with the development of dementia and may predispose patients to early-onset AD. 

Curative therapies do not exist for AD; thus, management centers on symptomatic treatment for neuropsychiatric or cognitive symptoms. Cholinesterase inhibitors and a partial N-methyl-D-aspartate antagonist are the standard medical therapies used in patients with AD. For patients with mild cognitive impairment or mild dementia, several newly approved antiamyloid therapies are also available. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021, and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Presently, both aducanumab and lecanemab are recommended only for the treatment of patients with mild cognitive impairment or mild dementia, the population in which their safety and efficacy were demonstrated in clinical trials. 

Psychotropic agents may be used to treat symptoms, such as depression, agitation, aggression, hallucinations, delusions, and sleep disorders, which can be problematic. Behavioral interventions may also be used, normally in combination with pharmacologic interventions (eg, anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations). Regular physical activity and exercise may help to delay disease progression and are recommended as an adjunct to the medical management of AD.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of Alzheimer's disease (AD), which probably was preceded by chronic traumatic encephalopathy (CTE).

AD is the most prevalent cause of cognitive impairment and dementia worldwide. Presently, approximately 50 million individuals are affected by AD; by 2050, the number of affected individuals globally is expected to reach 152 million. AD has a prolonged and progressive disease course that begins with neuropathologic changes in the brain years before onset of clinical manifestations. These changes include the accumulation of beta-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Neuroimaging studies have shown that beta-amyloid plaques begin to deposit in the brain ≥ 10 years before the start of cognitive decline. Patients with AD normally present with slowly progressive memory loss; as the disease progresses, other areas of cognition are affected. Patients may experience language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. Slowly progressive behavioral changes may also occur.

CTE is a neurodegenerative disorder that is believed to be the long-term consequence of repetitive head trauma. Its incidence is highest among athletes of high-impact sports, such as boxing or American football, and victims of domestic violence. Clinically, CTE can be indistinguishable from AD. Although neuropathologic differences exist, they can be confirmed only on postmortem examination. Patients with CTE may present with behavioral symptoms, such as aggression, depression, emotional lability, apathy, and suicidal feelings, as well as motor symptoms, including tremor, ataxia, incoordination, and dysarthria. Cognitive symptoms, including attention and concentration deficits and memory impairment, also occur. CTE is also associated with the development of dementia and may predispose patients to early-onset AD. 

Curative therapies do not exist for AD; thus, management centers on symptomatic treatment for neuropsychiatric or cognitive symptoms. Cholinesterase inhibitors and a partial N-methyl-D-aspartate antagonist are the standard medical therapies used in patients with AD. For patients with mild cognitive impairment or mild dementia, several newly approved antiamyloid therapies are also available. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021, and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Presently, both aducanumab and lecanemab are recommended only for the treatment of patients with mild cognitive impairment or mild dementia, the population in which their safety and efficacy were demonstrated in clinical trials. 

Psychotropic agents may be used to treat symptoms, such as depression, agitation, aggression, hallucinations, delusions, and sleep disorders, which can be problematic. Behavioral interventions may also be used, normally in combination with pharmacologic interventions (eg, anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations). Regular physical activity and exercise may help to delay disease progression and are recommended as an adjunct to the medical management of AD.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of advanced/metastatic breast cancer. 

Breast cancer is the most frequently diagnosed life-threatening cancer and the second-leading cause of cancer-related deaths in women worldwide. In the United States, an estimated 287,850 new cases of invasive breast cancer were diagnosed in 2022 and 43,250 women died of the disease. Globally, approximately 2.3 million new diagnoses and 685,000 breast cancer–related deaths were reported in 2020.

Tumor size, nodal spread, and distant metastases (TNM) at the time of diagnosis are key prognostic factors. Immunohistochemistry tumor markers (ie, estrogen receptor [ER], progesterone receptor [PR], and HER2), as well as grade and Ki-67 expression, have also been shown to be independent predictors of breast cancer death and are used together with TNM to guide treatment decisions. 

Despite advances in breast cancer diagnosis and treatment, metastatic recurrence remains a significant problem. Although the incidence of distance relapse is declining and survival times for patients with recurrent disease are improving, 20%-30% of patients with early breast cancer still die of metastatic disease. Metastatic breast cancer recurrence can arise months to decades after initial diagnosis and treatment. 

According to the National Comprehensive Cancer Network (NCCN) guidelines, biopsy is a critical component of the workup for patients with recurrent or stage IV disease. This is because biopsy ensures accurate determination of metastatic/recurrent disease and tumor histology and enables biomarker determination and selection of appropriate treatment. Soft-tissue tumor biopsy is preferred over bone sites unless a portion of the biopsy can be protected from harsh decalcification solution to preserve more accurate evaluation of biomarkers. Determination of HR status (ER and PR) and HER2 status should be repeated in all cases when diagnostic tissue is obtained because ER and PR assays may be falsely negative or falsely positive, and there may be discordance between the primary and metastatic tumors. According to the NCCN panel, re-testing the receptor status of recurrent disease should be performed, particularly when it was previously unknown, originally negative, or not overexpressed. 

Additionally, the staging evaluation of patients who present with recurrent or stage IV breast cancer should include history and physical exam; a complete blood cell count, liver function tests, chest diagnostic CT, bone scan, and radiography of any long or weight-bearing bones that are painful or appear abnormal on bone scan; diagnostic CT of the abdomen (with or without diagnostic CT of the pelvis) or MRI of the abdomen; and biopsy documentation of first recurrence whenever possible. The use of sodium fluoride PET or PET/CT for evaluating patients with recurrent disease is generally discouraged. 

Presently, metastatic breast cancer remains incurable. However, in recent years, the treatment landscape for metastatic breast cancer has significantly advanced in all breast cancer subtypes, leading to improvements in progression-free survival and even overall survival in some cases. For example, newer, targeted approaches directly address mutation drivers and allow precise delivery of chemotherapeutic agents. Detailed guidance on the treatment of breast cancer can be found here and in the full NCCN guidelines. 

Avan J. Armaghani, MD, Assistant Member, Department of Breast Oncology, Moffitt Cancer Center, University of South Florida, Tampa, FL.

Avan J. Armaghani, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of advanced/metastatic breast cancer. 

Breast cancer is the most frequently diagnosed life-threatening cancer and the second-leading cause of cancer-related deaths in women worldwide. In the United States, an estimated 287,850 new cases of invasive breast cancer were diagnosed in 2022 and 43,250 women died of the disease. Globally, approximately 2.3 million new diagnoses and 685,000 breast cancer–related deaths were reported in 2020.

Tumor size, nodal spread, and distant metastases (TNM) at the time of diagnosis are key prognostic factors. Immunohistochemistry tumor markers (ie, estrogen receptor [ER], progesterone receptor [PR], and HER2), as well as grade and Ki-67 expression, have also been shown to be independent predictors of breast cancer death and are used together with TNM to guide treatment decisions. 

Despite advances in breast cancer diagnosis and treatment, metastatic recurrence remains a significant problem. Although the incidence of distance relapse is declining and survival times for patients with recurrent disease are improving, 20%-30% of patients with early breast cancer still die of metastatic disease. Metastatic breast cancer recurrence can arise months to decades after initial diagnosis and treatment. 

According to the National Comprehensive Cancer Network (NCCN) guidelines, biopsy is a critical component of the workup for patients with recurrent or stage IV disease. This is because biopsy ensures accurate determination of metastatic/recurrent disease and tumor histology and enables biomarker determination and selection of appropriate treatment. Soft-tissue tumor biopsy is preferred over bone sites unless a portion of the biopsy can be protected from harsh decalcification solution to preserve more accurate evaluation of biomarkers. Determination of HR status (ER and PR) and HER2 status should be repeated in all cases when diagnostic tissue is obtained because ER and PR assays may be falsely negative or falsely positive, and there may be discordance between the primary and metastatic tumors. According to the NCCN panel, re-testing the receptor status of recurrent disease should be performed, particularly when it was previously unknown, originally negative, or not overexpressed. 

Additionally, the staging evaluation of patients who present with recurrent or stage IV breast cancer should include history and physical exam; a complete blood cell count, liver function tests, chest diagnostic CT, bone scan, and radiography of any long or weight-bearing bones that are painful or appear abnormal on bone scan; diagnostic CT of the abdomen (with or without diagnostic CT of the pelvis) or MRI of the abdomen; and biopsy documentation of first recurrence whenever possible. The use of sodium fluoride PET or PET/CT for evaluating patients with recurrent disease is generally discouraged. 

Presently, metastatic breast cancer remains incurable. However, in recent years, the treatment landscape for metastatic breast cancer has significantly advanced in all breast cancer subtypes, leading to improvements in progression-free survival and even overall survival in some cases. For example, newer, targeted approaches directly address mutation drivers and allow precise delivery of chemotherapeutic agents. Detailed guidance on the treatment of breast cancer can be found here and in the full NCCN guidelines. 

Avan J. Armaghani, MD, Assistant Member, Department of Breast Oncology, Moffitt Cancer Center, University of South Florida, Tampa, FL.

Avan J. Armaghani, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of advanced/metastatic breast cancer. 

Breast cancer is the most frequently diagnosed life-threatening cancer and the second-leading cause of cancer-related deaths in women worldwide. In the United States, an estimated 287,850 new cases of invasive breast cancer were diagnosed in 2022 and 43,250 women died of the disease. Globally, approximately 2.3 million new diagnoses and 685,000 breast cancer–related deaths were reported in 2020.

Tumor size, nodal spread, and distant metastases (TNM) at the time of diagnosis are key prognostic factors. Immunohistochemistry tumor markers (ie, estrogen receptor [ER], progesterone receptor [PR], and HER2), as well as grade and Ki-67 expression, have also been shown to be independent predictors of breast cancer death and are used together with TNM to guide treatment decisions. 

Despite advances in breast cancer diagnosis and treatment, metastatic recurrence remains a significant problem. Although the incidence of distance relapse is declining and survival times for patients with recurrent disease are improving, 20%-30% of patients with early breast cancer still die of metastatic disease. Metastatic breast cancer recurrence can arise months to decades after initial diagnosis and treatment. 

According to the National Comprehensive Cancer Network (NCCN) guidelines, biopsy is a critical component of the workup for patients with recurrent or stage IV disease. This is because biopsy ensures accurate determination of metastatic/recurrent disease and tumor histology and enables biomarker determination and selection of appropriate treatment. Soft-tissue tumor biopsy is preferred over bone sites unless a portion of the biopsy can be protected from harsh decalcification solution to preserve more accurate evaluation of biomarkers. Determination of HR status (ER and PR) and HER2 status should be repeated in all cases when diagnostic tissue is obtained because ER and PR assays may be falsely negative or falsely positive, and there may be discordance between the primary and metastatic tumors. According to the NCCN panel, re-testing the receptor status of recurrent disease should be performed, particularly when it was previously unknown, originally negative, or not overexpressed. 

Additionally, the staging evaluation of patients who present with recurrent or stage IV breast cancer should include history and physical exam; a complete blood cell count, liver function tests, chest diagnostic CT, bone scan, and radiography of any long or weight-bearing bones that are painful or appear abnormal on bone scan; diagnostic CT of the abdomen (with or without diagnostic CT of the pelvis) or MRI of the abdomen; and biopsy documentation of first recurrence whenever possible. The use of sodium fluoride PET or PET/CT for evaluating patients with recurrent disease is generally discouraged. 

Presently, metastatic breast cancer remains incurable. However, in recent years, the treatment landscape for metastatic breast cancer has significantly advanced in all breast cancer subtypes, leading to improvements in progression-free survival and even overall survival in some cases. For example, newer, targeted approaches directly address mutation drivers and allow precise delivery of chemotherapeutic agents. Detailed guidance on the treatment of breast cancer can be found here and in the full NCCN guidelines. 

Avan J. Armaghani, MD, Assistant Member, Department of Breast Oncology, Moffitt Cancer Center, University of South Florida, Tampa, FL.

Avan J. Armaghani, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.